NZ569087A

NZ569087A - Polycyclic indazole derivatives that are ERK inhibitors

Info

Publication number: NZ569087A
Application number: NZ569087A
Authority: NZ
Inventors: Alan Cooper; Yongqi Deng; Gerald W Shipps; Neng-Yang Shih; Hugh Zhu; Robert Sun; Joseph Kelly; Ronald Doll; Yang Nan; Tong Wang; Jagdish Desai; James Wang; Youhao Dong; Vincent S Madison; Li Xiao; Alan Hruza; M Arshad Siddiqui; Ahmed Samatar; Sunil Paliwal; Hon-Chung Tsui
Original assignee: Schering Corp
Priority date: 2005-12-13
Filing date: 2006-12-11
Publication date: 2011-09-30
Also published as: DK1966151T3; ZA200805525B; KR20080085018A; TW200732324A; EP1966151A1; EP1966151B1; JP2009519338A; US20070191604A1; CA2633023A1; AR056891A1; CY1112760T1; ES2372976T3; PE20100562A1; BRPI0619823A2; RU2442778C9; RU2008128119A; RU2442778C2; SI1966151T1; CA2633023C; BRPI0619823B1

Abstract

Disclosed is an indazole of formula 1.0 or the pharmaceutically acceptable salts thereof, wherein the substituents are defined the specification e.g. 1-{ 2-oxo-2-[4-(4-pyrimidin-2-yl-phenyl)-piperazin-1-yl]-ethy1} -pyrrolidine-3-carboxylic acid [3-(1H-imidazol-4-y1)-1H-indazol-5-y1]-amide for treating cancer.

Description

<div class="application article clearfix" id="description"> New Zealand Paient Spedficaiion for Paient Number 569087 RECIEVED IPONZ 22 AUGUST 2011 5 POLYCYCLIC INDAZOLE DERIVATIVES THAT ARE ERK INHIBITORS 10 BACKGROUND The processes involved in tumor growth, progression, and metastasis are mediated by signaling pathways that are activated in cancer cells. The ERK pathway plays a central role in regulating mammalian cell growth by relaying extracellular 15 signals from ligand-bound cell surface tyrosine kinase receptors such as erbB family, PDGF, FGF, and VEGF receptor tyrosine kinase. Activation of the ERK pathway is via a cascade of phosphorylation events that begins with activation of Ras. Activation of Ras leads to the recruitment and activation of Raf, a serine-threonine kinase. Activated Raf then phosphorylates and activates MEK1/2, which then phosphorylates 20 and activates ERK1/2. When activated, ERK1/2 phosphorylates several downstream targets involved in a multitude of cellular events including cytoskeletal changes and transcriptional activation. The ERK/MAPK pathway is one of the most important for cell proliferation, and it is believed that the ERK/MAPK pathway is frequently activated in many tumors. Ras genes, which are upstream of ERK1/2, are mutated in several 25 cancers including colorectal, melanoma, breast and pancreatic tumors. The high Ras activity is accompanied by elevated ERK activity in many human tumors. In addition, mutations of BRAF, a serine-threonine kinase of the Raf family, are associated with increased kinase activity. Mutations in BRAF have been identified in melanomas (60%), thyroid cancers (greater than 40%) and colorectal cancers. These 30 observations indicate that the ERK1/2 signalling pathway is an attractive pathway for anticancer therapies in a broad spectrum of human tumours. Therefore, a welcome contribution to the art would be small-molecules (i.e., compounds) that inhibit ERK activity (i.e., ERK1 and ERK2 activity), which small-molecules would be useful for treating a broad spectrum of cancers, such as, for 35 example, melanoma, pancreatic cancer, thryroid cancer, colorectal cancer, lung RECIEVED IPONZ 22 AUGUST 2011 -2- cancer, breast cancer, and ovarian cancer. Such a contribution is provided by this invention, or at least the public is provided with a useful choice. SUMMARY OF THE INVENTION This invention provides compounds that inhibit the activity of ERK1 and/or the activity of ERK2. The compounds of this invention also inhibit the phosphorylation of ERK1 and ERK2. Thus, this invention provides compounds that are ERK inhibitors (i.e., ERK1 inhibitors and/or ERK2 inhibitors), said compounds being of the formula 1.0: or the pharmaceutical^ acceptable salts thereof, wherein: Y1, Y2, and Y3 are each independently selected from the group consisting of: -CH=, -N= and -CR9=; z is 1 to 3; Q is a substituent selected from the group consisting of: (2.5) (2.6) (2.7) (2.8) recieved iponz 22 august 2011 3- (2.9) (2.10) (2.11) Q' r5 r4 r4 (2.12) (2.13) (2.14) (2.15) (2.16) rZ r7 \ n X/ (2.17) r5 r5a w r6 ■r6 •r5 r5a (2.18) j3 | ^Z-| 5A , r4 r4 (2.19) (2.20) (2.21) rl -r7 and R (2.22) Each Q represents a ring independently selected from the group consisting of: cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl, wherein said substituted rings are substituted with 1 to 3 substituents independently selected from the group consisting of: the R10 moieties; provided that when Q1 is aryl, heteroaryl, substituted RECIEVED IPONZ 22 AUGUST 2011 -4 - aryl or substituted heteroaryl then the carbon atoms at the ring junction are not substituted; substituted cycloalkyl, heterocycloalkyl, and substituted heterocycloalkyl, wherein said substituted rings are substituted with 1 to 3 substituents independently selected from the group consisting of: the R10 moieties; Z1 represents -(C(R24)2)W- wherein each R24 is independently selected from the group consisting of: H, alkyl and F, and wherein w is 1, 2 or 3; Z2 is selected from the group consisting of: -N(R44)-, -O- and -C(R46)2-; m is 1 to 6; n is 1 to 6; p is 0 to 6; t is 0, 1, or 2; R1 is selected from the group consisting of: (1) -CN, (2) -N02, (3) -OR10, (4) -SR10, (5) -N(R10)2, (6) R10, (7) -C(0)R1°, (8) -(C(R30)2)n-NR32-C(O)-R10, (9)-(C(R30)2)n-NR32-S(O)rR10, (10)-(C(R30)2)n-NR32-C(0)-N(R32)-R10, (11) Q2 represents a ring selected from the group consisting of: cycloalkyl, o (12) -CF3, (13) -C(0)0R1° RECIEVED IPONZ 22 AUGUST 2011 -5 - (14) -(C(R30)2)nR13 wherein n is 1, each R30 is H, and R13 is selected from the group consisting of: -OH and -N(R10)2, wherein each R10 is independently selected, (15) alkenyl, (16) -NR32-C(0)-R14, (17) r10 —n-c-n(r10)2 o wherein each R10 is independently selected, (18) r10 —N—S(0)t—R10 wherein each R10 is independently selected, (19) r nh ?—C—N—R15 * r32 , (20) -C(O)-NR32-(C(R30)2)p-OR10, (21) -C(O)N(R10)2 wherein each R10 is independently selected, (22) -C(0)-NR32-C(R18)3 wherein each R18 is independently selected from the group consisting of: R10 and -C(0)0R19, and R19 is selected from the group consisting of: alkyl and substituted arylalkyl, (23) -C(O)-NR32-(C(R30)2)n-C(O)-N(R10)2, (24) heterocycloalkenyl, (25) (26) arylalkenyl-; R2 is selected from the group consisting of: (1) H, (2) -CN, (3) halo, RECIEVED IPONZ 22 AUGUST 2011 -6 - (4) alkyl, (5) substituted alkyl wherein said substituted alkyl is substituted with 1 to 3 substitutents selected from the group consisting of: (a) -OH, (b) -O-alkyl, (c) -O-alkyl substituted with 1 to 3 F atoms, and (d) -N(R40)2 wherein each R40 is independently selected from the group consisting of: (i) H, (ii) C1-C3 alkyl, (iii) -CF3, and (e) halo, (6) alkynyl, (7) alkenyl, (8) -(CH2)mR11, (9) -N(R26)2, (10)-OR23, (11)-N(R26)C(0)R42, (12) cycloalkyl, (13) cycloalkylalkyl, (14)|-(C(R30)2)n-N^z2 (15)-0-(substituted alkyl) wherein said substituted alkyl is substituted with 1 to 3 F atoms, (16) -S(0)t-alkyl, (17) -C(0)-alkyl, (18) N—O—H II C—alkyl (19) N—O—alkyl II —C—alkyl wherein each alkyl is independently selected, (20) o H II N—N—C—alkyl II —C—alkyl which each alkyl is independently selected, (21) RECIEVED IPONZ 22 AUGUST 2011 -7- alkyl O II N—N—C—alkyl 5 II d —C—alkyl wherein each alkyl is independently selected, (22) -N(R48)-C(0)-R48 wherein each R48 is independently selected from the group consisting of: H and alkyl, and (23) -C(0)-alkyl: each R3, R4, R5, R6 and R7 is independently selected from the group consisting of: (1) H, (2) alkenyl, (3) substituted alkenyl, (4) alkyl, (5) substituted alkyl, (6) cycloalkyl, (7) substituted cycloalkyl, (8) cycloalkylalkyl-, (9) substituted cycloalkylalkyl-, (10) heterocycloalkyl, (11) substituted heterocycloalkyl, (12) heterocycloalkylalkyl-, (13) substituted heterocycloalkylalkyl-, (14) -C(0)R1°, (15) arylheteroaryl-, (16) substituted arylheteroaryl-, (17) heteroarylaryl-, (18) substituted heteroarylaryl-, (19) aryl, (20) substituted aryl, (21) heteroaryl, (22) substituted heteroaryl, (23) heteroarylheteroaryl-, (24) substituted heteroarylheteroaryl-, RECIEVED IPONZ 22 AUGUST 2011 -8- (25) arylaminoheteroaryl-, (26) substituted arylaminoheteroaryl-, (27) arylalkynyl-, (28) substituted arylalkynyl-, 5 (29) heteroarylalkynyl-, (30) substituted heteroarylalkynyl-, wherein said R3, R4, R5, R6 and R7 substituted groups (7), (9), (11), (13), (16), (18), (20), (22), (24), (26), (28) and (30) are substituted with 1 to 3 substituents independently selected from the group consisting of: -NH2, alkyl, alkenyl, halo, 10 -C(0)-NH-R28, -C(0)0R28, and -C(0)R28, and wherein said R3, R4, R5, R6 and R7 substituted groups (3) and (5) are substituted with 1 to 3 substituents independently selected from the group consisting of: -NH2, halo, -C(0)-NH-R28, -C(0)0R28, and -C(0)R28; R5A is selected from the group consisting of: halo, -OH, and -O-alkyl; 15 R8 is selected from the group consisting of: H, -OH, -N(R10)2, -NR10C(O)R12, and alkyl; each R9 is independently selected from the group consisting of:halogen, -CN, -N02, -OR10, -SR10, -N(R10)2, and R10; each R10 is independently selected from the group consisting of: H, alkyl, aryl, 20 arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, alkylheteroaryl-, alkylaryl-, substituted alkyl, substituted aryl, substituted arylalkyl, substituted heteroaryl, substituted heteroarylalkyl, substituted cycloalkyl, substituted cycloalkylalkyl, substituted heterocycloalkyl, substituted heterocycloalkylalkyl, substituted alkylheteroaryl-, substituted alkylaryl-, 25 heterocycloalkenyl, and substituted heterocycloalkenyl, and wherein: said R10 substituted alkyl is substituted with 1 to 3 substituents independently selected from the group consisting of: -NH2, -NHR20, -N02, -CN, -OR26, halo, -C(0)-NH-R26, -C(0)0R26, and -C(0)R26, and said R10 substituted aryl, substituted arylalkyl, substituted heteroaryl, 30 substituted heteroarylalkyl, substituted cycloalkyl, substituted cycloalkylalkyl, substituted heterocycloalkyl, substituted heterocycloalkylalkyl, substituted alkylheteroaryl- and substituted alkylaryl- are substituted with 1 to 3 substituents independently selected from the group consisting of: (1) -NH2, (2) -N02, (3) -CN, (4) -OH, (5) -OR20, (6) -OCF3, (7) alkyl substituted with 1 to 3 independently selected RECIEVED IPONZ 22 AUGUST 2011 -9- halo atoms, (8) -C(0)R38, (9) alkyl, (10) alkenyl, (11) halo, (12) -C(0)-NH-R26, (13) -C(0)0R38, (14) -C(O)-NR32-(C(R30)2)n-N(R38)2, (15) -S(0)tR38, (16) -C(0)-NR32-R38, (17) -NR32-C(0)-R38, c n r32 08) |—c-n-r38 > 5 (19) -NHR20, and (20) cycloalkyl; R11 is selected from the group consisting of: F, -OH, -CN, -OR10, -NHNR1R10, -SR10 and heteroaryl; R12 is selected from the group consisting of: alkyl, aryl, heteroaryl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl and heterocycloalkylalkyl; 10 R14 is selected from the group consisting of: alkyl, aryl, heteroaryl, cycloalkyl, cycloalkylalkyl-, heterocycloalkyl, alkylheterocycloalkyl, heterocycloalkylalkyl-, alkylheteroaryl- and alkylaryl-; R15 is selected from the group consisting of: H, -OH, alkyl, aryl, heteroaryl, cycloalkyl, cycloalkylalkyl-, heterocycloalkyl and heterocycloalkylalkyl-, alkylheteroaryl-15 and alkylaryl-; R20 represents alkyl; pQ R is selected from the group consisting of: H, alkyl, aryl, cycloalkyl, and cycloalkylalkyl-; each R26 is independently selected from the group consisting of: H and alkyl; 20 R28 is alkyl; each R30 is independently selected from the group consisting of: H, alkyl, and F; each R32 is independently selected from the group consisting of: H and alkyl, and wherein each R32 is generally H; 25 each R35 is independently selected from the group consisting of: H and Ci to C6 alkyl; R36 is selected from the group consisting of: H, alkyl, and -O-alkyl; oo each R is independently selected from the group consisting of: H, alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, 30 heterocycloalkylalkyl, alkylheteroaryl-, alkylaryl-, substituted alkyl, substituted aryl, substituted arylalkyl, substituted heteroaryl, substituted heteroarylalkyl, substituted cycloalkyl, substituted cycloalkylalkyl, substituted heterocycloalkyl, substituted RECIEVED IPONZ 22 AUGUST 2011 - 10 - heterocycloalkylalkyl, substituted alkylheteroaryl- and substituted alkylaryl-, and wherein: said R38 substituted alkyl is substituted with 1 to 3 substituents independently selected from the group consisting of: -NH2, -N02, -CN, -OR26, halo, -C(0)-NH-R28, 5 -C(0)0R28, and -C(0)R28, and said R38 substituted aryl, substituted arylalkyl, substituted heteroaryl, substituted heteroarylalkyl, substituted cycloalkyl, substituted cycloalkylalkyl, substituted heterocycloalkyl, substituted heterocycloalkylalkyl, substituted alkylheteroaryl- and substituted alkylaryl- are substituted with 1 to 3 substituents 10 independently selected from the group consisting of: (1) -NH2, (2) -N02, (3) -CN, (4) -OH, (5) -OR20, (6) -OCF3, (7) -CF3, (8) -C(0)R26, (9) alkyl, (10) alkenyl, (11) halo, (12) -C(0)-NH-R26, (13) -C(0)0R26, (14) -C(O)-NR32-(C(R30)2)n-N(R26)2, (15) -S(0)tR26, (16) -C(0)N(R32)(R26), (17) -NR32C(0)R26, ; and 15 (19) -NHR20; R42 is selected from the group consisting of: alkyl, aryl, heteroaryl, and cycloalkyl; R44 is selected from the group consisting of: H, alkyl, cycloalkyl, and cycloalkylalkyl; and 20 Each R46 is independently selected from the group consisting of: H, alkyl, cycloalkyl, and cycloalkylalkyl. 25 or the pharmaceutical^ acceptable salts thereof, wherein: Y1, Y2, and Y3 are each independently selected from the group consisting of: C, N and substituted carbon; Also described are compounds of formula 1:0: RECIEVED IPONZ 22 AUGUST 2011 - 11 - Q is selected from the group consisting of: piperidinyl, piperazinyl, tetrahydropyridinyl (e.g., 1,2,3,6-tetrahydopyridinyl), bridged piperazinyl, bridged piperidinyl, bridged tetrahydropyridinyl, substituted piperidinyl, substituted piperazinyl, substituted tetrahydropyridinyl (e.g., a substituted 1,2,3,6-tetrahydo-pyridinyl), bridged substituted piperazinyl, bridged substituted piperidinyl, and bridged substituted tetrahydropyridinyl; z is 1 to 3 (and preferably 1); and R1, R2, R8, R35 and R36 are as defined below. This invention provides compounds of formula 1.0 of the invention (for example, as described in any one of Embodiment Nos. 1 to 106) in pure or isolated form. This invention also provides a pharmaceutical composition comprising an effective amount of at least one (e.g., 1, 2 or 3, 1 or 2, and usually 1) compound of formula 1.0 of the invention (for example, as described in any one of Embodiment Nos. 1 to 161) and a pharmaceutically acceptable carrier. This invention also provides a pharmaceutical composition comprising an effective amount of at least one (e.g., 1, 2 or 3, 1 or 2, and usually 1) compound of formula 1.0 of the invention (for example, as described in any one of Embodiment Nos. 1 to 161) and an effective amount of at least one other (e.g., 1, 2 or 3, 1 or 2, and usually 1) pharmaceutically active ingredient (such as, for example, a chemotherapeutic agent), and a pharmaceutically acceptable carrier. Accordingly, the invention also provides a pharmaceutical composition comprising at least one compound of the invention or a pharmaceutically acceptable salt thereof, at least one chemotherapeutic agent, and a pharmaceutically acceptable carrier. The invention also provides a pharmaceutical composition comprising at least one compound of the invention or a pharmaceutically acceptable salt thereof, at least one signal transduction inhibitor, and a pharmaceutically acceptable carrier. The invention a pharmaceutical composition comprising at least one compound of the invention or a pharmaceutically acceptable salt thereof, antihormonal agents, and a pharmaceutically acceptable carrier. The invention also relates to a compound of the invention, or a pharmaceutically acceptable salt thereof, for use as a medicament. The invention also relates to a use of at least one compound of the invention, RECIEVED IPONZ 22 AUGUST 2011 - 12- or a pharmaceutically acceptable salt thereof: (A) for the manufacture of a medicament for treating cancer; (B) for the manufacture of a medicament for treating cancer, wherein said medicament is in a form for administration with at least one chemotherapeutic agent; (C) for the manufacture of a medicament for treating cancer, said medicament is in a form for administration with at least one chemotherapeutic agent, and radiation therapy; or (D) and at least one chemotherapeutic agent for the manufacture of a medicament for treating cancer. The invention also relates to a use of at least one compound of the invention, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating cancer, wherein said medicament is in a form for administration with at least one chemotherapeutic agent selected from the group consisting of: (1) taxanes, (2) platinum coordinator compounds, (3) epidermal growth factor (EGF) inhibitors that are antibodies, (4) EGF inhibitors that are small molecules, (5) vascular endolithial growth factor (VEGF) inhibitors that are antibodies, (6) VEGF kinase inhibitors that are small molecules, (7) estrogen receptor antagonists or selective estrogen receptor modulators (SERMs), (8) anti-tumor nucleoside derivatives, (9) epothilones, (10) topoisomerase inhibitors, (11) vinca alkaloids, (12) antibodies that are inhibitors of ocVp3 integrins, (13) folate antagonists, (14) ribonucleotide reductase inhibitors, (15) anthracyclines, (16) biologies; (17) inhibitors of angiogenesis and/or suppressors of tumor necrosis factor alpha (TNF-alpha), (18) Bcr/abl kinase inhibitors, (19) MEK1 and/or MEK 2 inhibitors that are small molecules, (20) IGF-1 and IGF-2 inhibitors that are small molecules, (21) small molecule inhibitors of RAF and BRAF kinases, (22) small molecule inhibitors of cell cycle dependent kinases such as CDK1, CDK2, CDK4 and CDK6, (23) alkylating agents, and (24) farnesyl protein transferase inhibitors. The invention also relates to a use of a compound of the invention, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating cancer, wherein said medicament is in a form for administration with at least one signal transduction inhibitor. The invention also relates to a use of at least one compound of the invention, or a pharmaceutically acceptable salt thereof: RECIEVED IPONZ 22 AUGUST 2011 - 13- (A) for the manufacture of a medicament for treating cancer wherein said cancer is selected from the group consisting of: lung cancer, pancreatic cancer, colon cancer, myeloid leukemias, thyroid cancer, myelodysplastic syndrome, bladder carcinoma, epidermal carcinoma, melanoma, breast cancer, prostate cancer, head 5 and neck cancers, ovarian cancer, brain cancers, cancers of mesenchymal origin, sarcomas, tetracarcinomas, nuroblastomas, kidney carcinomas, hepatomas, non-Hodgkin's lymphoma, multiple myeloma, and anaplastic thyroid carcinoma; (B) for the manufacture of a medicament for treating cancer wherein said cancer is selected from the group consisting of: melanoma, pancreatic cancer, 10 thryroid cancer, colorectal cancer, lung cancer, breast cancer, and ovarian cancer; (C) for the manufacture of a medicament for treating cancer wherein said medicament is in a form for administration in combination with at least one chemotherapeutic agent, and wherein said cancer is selected from the group consisting of: melanoma, pancreatic cancer, thryroid cancer, colorectal cancer, lung 15 cancer, breast cancer, and ovarian cancer; or (D) in combination with at least one chemotherapeutic agent for the manufacture of a medicament for treating cancer wherein said cancer is selected from the group consisting of: melanoma, pancreatic cancer, thyroid cancer, colorectal cancer, lung cancer, breast cancer, and ovarian cancer. 20 The invention also relates to a use of at least one compound of the invention, or a pharmaceutically acceptable salt thereof: (A) for the manufacture of a medicament for treating melanoma; (B) for the manufacture of a medicament for treating melanoma, wherein said medicament is in a form for administration in combination with at least one 25 chemotherapeutic agent; (B) in combination with at least one chemotherapeutic agent for the manufacture of a medicament for treating melanomas; (C) for the manufacture of a medicament for treating pancreatic cancer; (D) for the manufacture of a medicament for treating pancreatic cancer, 30 wherein said medicament is in a form for administration with at least one chemotherapeutic agent; (D') in combination with at least one chemotherapeutic agent for the manufacture of a medicament for pancreatic cancer; (E) for the manufacture of a medicament for treating thyroid cancer; RECIEVED IPONZ 22 AUGUST 2011 - 14 - (F) for the manufacture of a medicament for treating thyroid cancer, wherein said medicament is in a form for administration in combination with at least one chemotherapeutic agent; (F) in combination with at least one chemotherapeutic agent for the 5 manufacture of a medicament for treating thyroid cancer; (G) for the manufacture of a medicament for treating colorectal cancer; (H) for the manufacture of a medicament for treating colorectal cancer, wherein said medicament is in a form for administration in combination with at least one chemotherapeutic agent; 10 (H') in combination with at least one chemotherapeutic agent for the manufacture of a medicament for treating colorectal cancer; (I) for the manufacture of a medicament for treating lung cancer; (J) for the manufacture of a medicament for treating lung cancer, wherein said medicament is in a form for administration in combination with at least 15 one chemotherapeutic agent; (J) in combination with at least one chemotherapeutic agent for the manufacture of a medicament for treating lung cancer; (K) for the manufacture of a medicament for treating breast cancer; (L) for the manufacture of a medicament for treating breast cancer, 20 wherein said medicament is in a form for administration in combination with at least one chemotherapeutic agent; (L') in combination with at least one chemotherapeutic agent for the manufacture of a medicament for treating breast cancer; (M) for the manufacture of a medicament for treating ovarian cancer; 25 (N) for the manufacture of a medicament for treating ovarian cancer, wherein said medicament is in a form for administration in combination with at least one chemotherapeutic agent; (NT) in combination with at least one chemotherapeutic agent for the manufacture of a medicament for treating ovarian cancer; 30 (O) for the manufacture of a medicament for treating hormone- dependent breast cancer, wherein said medicament is in a form for administration in combination with antihormonal agents; (O') in combination with antihormonal agents for the manufacture of a medicament for treating hormone-dependent breast cancer; RECIEVED IPONZ 22 AUGUST 2011 - 15 - (P) for the manufacture of a medicament for treating hormone-dependent breast cancer, wherein said medicament is in a form for administration in combination with antihormonal agents, and in combination with at least one chemotherapeutic agent; 5 (P') in combination with at least one chemotherapeutic agent for the manufacture of a medicament for treating hormone-dependent breast cancer; (Q) for the manufacture of a medicament for preventing hormone-dependent breast cancer, wherein said medicament is in a form for administration in combination with antihormonal agents; 10 (Q') in combination with antihormonal agents for the manufacture of a medicament for treating hormone-dependent breast cancer; (R) for the manufacture of a medicament for preventing hormone-dependent breast cancer, wherein said medicament is in a form for administration in combination with antihormonal agents, and in combination with at least one 15 chemotherapeutic agent; (R') in combination with at least one chemotherapeutic agent for the manufacture of a medicament for preventing hormone-dependent breast cancer; (S) for the manufacture of a medicament for treating brain cancer; (T) for the manufacture of a medicament for treating brain cancer, 20 wherein said medicament is in a form for administration in combination with at least one chemotherapeutic agent; (T) in combination with at least one chemotherapeutic agent for the manufacture of a medicament for treating brain cancer; (U) for the manufacture of a medicament for treating brain cancer, 25 wherein said medicament is in a form for administration in combination with a chemotherapeutic agent wherein said chemotherapeutic agent is temozolomide; (U') in combination with a chemotherapeutic agent wherein said chemotherapeutic agent is temozolomide for the manufacture of a medicament for treating brain cancer; 30 (V) for the manufacture of a medicament for treating prostate cancer; (W) for the manufacture of a medicament for treating prostate cancer, wherein said medicament is in a form for administration in combination with at least one chemotherapeutic agent; RECIEVED IPONZ 22 AUGUST 2011 - 16- (W) in combination with at least one chemotherapeutic agent for the manufacture of a medicament for treating prostate cancer; (X) for the manufacture of a medicament for treating myelodysplastic syndrome ; 5 (Y) for the manufacture of a medicament for treating myelodysplastic syndrome, wherein said medicament is in a form for administration in combination with at least one chemotherapeutic agent; (Y) in combination with at least one chemotherapeutic agent for the manufacture of a medicament for treating myelodysplastic syndrome; 10 (Z) for the manufacture of a medicament for treating myeloid leukemias; (AA) for the manufacture of a medicament for treating myeloid leukemias, wherein said medicament is in a form for administration in combination with at least one chemotherapeutic agent; (AA) in combination with at least one chemotherapeutic agent for the 15 manufacture of a medicament for treating, myeloid leukemias; (AB) for the manufacture of a medicament for treating acute myelogenous leukemia; (AC) for the manufacture of a medicament for treating acute myelogenous leukemia, wherein said medicament is in a form for administration in 20 combination with at least one chemotherapeutic agent; (AC') in combination with at least one chemotherapeutic agent for the manufacture of a medicament for treating acute myelogenous leukemia; (AD) for the manufacture of a medicament for treating chronic myelomonocytic leukemia; 25 (AE) for the manufacture of a medicament for treating chronic myelomonocytic leukemia, wherein said medicament is in a form for administration in combination with at least one chemotherapeutic agent; (AE') in combination with at least one chemotherapeutic agent for the manufacture of a medicament for treating chronic myelomonocytic leukemia; 30 (AF) for the manufacture of a medicament for treating chronic myelogenous leukemia; (AG) for the manufacture of a medicament for treating chronic myelogenous leukemia, wherein said medicament is in a form for administration in combination with at least one chemotherapeutic agent; RECIEVED IPONZ 22 AUGUST 2011 - 17- (AG) in combination with at least one chemotherapeutic agent for the manufacture of a medicament for treating chronic myelogenous leukemia; (AH) for the manufacture of a medicament for treating bladder cancer; (AI) for the manufacture of a medicament for treating bladder cancer, wherein said medicament is in a form for administration in combination with at least one chemotherapeutic agent; (Al) in combination with at least one chemotherapeutic agent for the manufacture of a medicament for treating bladder cancer; (AJ) for the manufacture of a medicament for treating non-Hodgkin's lymphoma; (AK) for the manufacture of a medicament for treating non-Hodgkin's lymphoma, wherein said medicament is in a form for administration in combination with at least one chemotherapeutic agent; (AK') in combination with at least one chemotherapeutic agent for the manufacture of a medicament for treating non-Hodgkin's lymphoma; (AL) for the manufacture of a medicament for treating multiple myeloma RECIEVED IPONZ 22 AUGUST 2011 -18- (AM) for the manufacture of a medicament for treating multiple myeloma, wherein said medicament is in a form for administration in combination at least one chemotherapeutic agent; or (AM') in combination with at least one chemotherapeutic agent for the manufacture of a medicament for treating multiple myeloma. The invention also relates to a use of at least one compound of the invention for the manufacture of a medicament for treating cancer wherein the medicament when administered is administered with at least one chemotherapeutic agent. The invention also relates to a use of at least one compound of the invention and at least one chemotherapeutic agent for the manufacture of a medicament for treating cancer. Also described is a method of inhibiting ERK (i.e., inhibiting the activity of ERK) in a patient in need of such treatment comprising administering to said patient an effective amount of at least one (e.g., 1, 2 or 3, 1 or 2, and usually 1) compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 161). Also described is a method of inhibiting ERK1 (i.e., inhibiting the activity of ERK1) in a patient in need of such treatment comprising administering to said patient an effective amount of at least one (e.g., 1, 2 or 3, 1 or 2, and usually 1) compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 161). Also described is a method of inhibiting ERK2 (i.e., inhibiting the activity of ERK2) in a patient in need of such treatment comprising administering to said patient an effective amount of at least one (e.g., 1, 2 or 3, 1 or 2, and usually 1) compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 161). Also described is a method of inhibiting ERK1 and ERK2 (i.e., inhibiting the activity of ERK1 and ERK2) in a patient in need of such treatment comprising administering to said patient an effective amount of at least one (e.g., 1, 2 or 3, 1 or 2, and usually 1) compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 161). Also described is a method for treating cancer in a patient in need of such treatment, said method comprising administering to said patient an effective amount RECIEVED IPONZ 22 AUGUST 2011 -19- of at least one (e.g., 1, 2 or 3, 1 or 2, and usually 1) compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 161). Also described is a method for treating cancer in a patient in need of such treatment, said method comprising administering to said patient an effective amount of a pharmaceutical composition comprising an effective amount of at least one (e.g., 1, 2 or 3, 1 or 2, and usually 1) compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 161). Also described is a method for treating cancer in a patient in need of such treatment, said method comprising administering to said patient an effective amount of at least one (e.g., 1, 2 or 3, 1 or 2, and usually 1) compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 161), in combination with an effective amount of at least one (e.g., 1, 2 or 3, 1 or 2, or 1) chemotherapeutic agent. Also described is a method for treating cancer in a patient in need of such treatment, said method comprising administering to said patient an effective amount of a pharmaceutical composition comprising an effective amount of at least one (e.g., 1, 2 or 3, 1 or 2, and usually 1) compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 161), in combination with an effective amount of at least one (e.g., 1, 2 or 3, 1 or 2, or 1) chemotherapeutic agent. Also described is a method of treating cancer in a patient in need of such treatment, said method comprising administering to said patient an effective amount of at least one (e.g., 1, 2 or 3, 1 or 2, and usually 1) compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 161) in combination with at least one (e.g., 1, 2 or 3, 1 or 2, and usually 1) signal transduction inhibitor. Also described is a method of treating cancer in a patient in need of such treatment, said method comprising administering to said patient an effective amount of a pharmaceutical composition comprising an effective amount of at least one (e.g., 1, 2 or 3, 1 or 2, and usually 1) compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 161) in combination with at least one (e.g., 1, 2 or 3, 1 or 2, and usually 1) signal transduction inhibitor. Also described is a method for treating lung cancer, pancreatic cancer, colon cancer (e.g., colorectal cancer), myeloid leukemias (e.g., AML, CML, and CMML), thyroid cancer, myelodysplastic syndrome (MDS), bladder carcinoma, epidermal carcinoma, melanoma, breast cancer, prostate cancer, head and neck cancers (e.g., RECIEVED IPONZ 22 AUGUST 2011 -20- squamous cell cancer of the head and neck), ovarian cancer, brain cancers (e.g., gliomas, such as glioma blastoma multiforme), cancers of mesenchymal origin (e.g., fibrosarcomas and rhabdomyosarcomas), sarcomas, tetracarcinomas, nuroblastomas, kidney carcinomas, hepatomas, non-Hodgkin's lymphoma, multiple 5 myeloma, or anaplastic thyroid carcinoma, in a patient in need of such treatment, said method comprising administering to said patient an effective amount of at least one (e.g., 1, 2 or 3, 1 or 2, and usually 1) compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 161). Also described is a method for treating lung cancer, pancreatic cancer, colon 10 cancer (e.g., colorectal cancer), myeloid leukemias (e.g., AML, CML, and CMML), thyroid cancer, myelodysplastic syndrome (MDS), bladder carcinoma, epidermal carcinoma, melanoma, breast cancer, prostate cancer, head and neck cancers (e.g., squamous cell cancer of the head and neck), ovarian cancer, brain cancers (e.g., gliomas, such as glioma blastoma multiforme), cancers of mesenchymal origin (e.g., 15 fibrosarcomas and rhabdomyosarcomas), sarcomas, tetracarcinomas, nuroblastomas, kidney carcinomas, hepatomas, non-Hodgkin's lymphoma, multiple myeloma, or anaplastic thyroid carcinoma in a patient in need of such treatment, said method comprising administering to said patient an effective amount of at least one (e.g., 1, 2 or 3, 1 or 2, and usually 1) compound of formula 1.0 (for example, as 20 described in any one of Embodiment Nos. 1 to 161), in combination with an effective amount of at least one (e.g., 1, 2 or 3, 1 or 2, or 1) chemotherapeutic agent. Also described is a method for treating lung cancer, pancreatic cancer, colon cancer (e.g., colorectal cancer), myeloid leukemias (e.g., AML, CML, and CMML), thyroid cancer, myelodysplastic syndrome (MDS), bladder carcinoma, epidermal 25 carcinoma, melanoma, breast cancer, prostate cancer, head and neck cancers (e.g., squamous cell cancer of the head and neck), ovarian cancer, brain cancers (e.g., gliomas, such as glioma blastoma multiforme), cancers of mesenchymal origin (e.g., fibrosarcomas and rhabdomyosarcomas), sarcomas, tetracarcinomas, nuroblastomas, kidney carcinomas, hepatomas, non-Hodgkin's lymphoma, multiple 30 myeloma, or anaplastic thyroid carcinoma in a patient in need of such treatment, said method comprising administering to said patient an effective amount of a pharmaceutical composition comprising an effective amount of at least one (e.g., 1, 2 or 3, 1 or 2, and usually 1) compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 161). RECIEVED IPONZ 22 AUGUST 2011 -21 - Also described is a method for treating lung cancer, pancreatic cancer, colon cancer (e.g., colorectal cancer), myeloid leukemias (e.g., AML, CML, and CMML), thyroid cancer, myelodysplastic syndrome (MDS), bladder carcinoma, epidermal carcinoma, melanoma, breast cancer, prostate cancer, head and neck cancers (e.g., 5 squamous cell cancer of the head and neck), ovarian cancer, brain cancers (e.g., gliomas, such as glioma blastoma multiforme), cancers of mesenchymal origin (e.g., fibrosarcomas and rhabdomyosarcomas), sarcomas, tetracarcinomas, nuroblastomas, kidney carcinomas, hepatomas, non-Hodgkin's lymphoma, multiple myeloma, or anaplastic thyroid carcinoma in a patient in need of such treatment, said 10 method comprising administering to said patient an effective amount of a pharmaceutical composition comprising an effective amount of at least one (e.g., 1, 2 or 3, 1 or 2, and usually 1) compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 161), in combination with an effective amount of at least one (e.g., 1, 2 or 3, 1 or 2, or 1) chemotherapeutic agent. 15 Also described is a method for treating cancer in a patient in need of such treatment, said method comprising administering to said patient an effective amount of at least one (e.g., 1, 2 or 3, 1 or 2, and usually 1) compound of formula 1.0 (for example, as described in anyone of Embodiment Nos. 1 to 161), wherein said cancer is selected from the group consisting of: melanoma, pancreatic cancer, thryroid 20 cancer, colorectal cancer, lung cancer, breast cancer, and ovarian cancer. Also described is a method for treating cancer in a patient in need of such treatment, said method comprising administering to said patient an effective amount of at least one (e.g., 1, 2 or 3, 1 or 2, and usually 1) compound of formula 1.0 (for example, as described in anyone of Embodiment Nos. 1 to 161), in combination with 25 an effective amount of at least one (e.g., 1, 2 or 3, 1 or 2, or 1) chemotherapeutic agent wherein said cancer is selected from the group consisting of: melanoma, pancreatic cancer, thryroid cancer, colorectal cancer, lung cancer, breast cancer, and ovarian cancer. Also described is a method for treating cancer in a patient in need of such 30 treatment, said method comprising administering to said patient an effective amount of a pharmaceutical composition comprising an effective amount of at least one (e.g., 1, 2 or 3, 1 or 2, and usually 1) compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 161), wherein said cancer is selected from the RECIEVED IPONZ 22 AUGUST 2011 -22- group consisting of: melanoma, pancreatic cancer, thryroid cancer, colorectal cancer, lung cancer, breast cancer, and ovarian cancer. Also described is a method for treating cancer in a patient in need of such treatment, said method comprising administering to said patient an effective amount 5 of a pharmaceutical composition comprising an effective amount of at least one (e.g., 1, 2 or 3, 1 or 2, and usually 1) compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 161), in combination with an effective amount of at least one (e.g., 1, 2 or 3, 1 or 2, or 1) chemotherapeutic agent wherein said cancer is selected from the group consisting of: melanoma, pancreatic cancer, thryroid cancer, 10 colorectal cancer, lung cancer, breast cancer, and ovarian cancer. Also described is a method for treating melanoma in a patient in need of such treatment, said method comprising administering to said patient an effective amount of at least one (e.g., 1, 2 or 3, 1 or 2, and usually 1) compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 161). 15 Also described is a method for treating melanoma in a patient in need of such treatment, said method comprising administering to said patient an effective amount of at least one (e.g., 1, 2 or 3, 1 or 2, and usually 1) compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 161), in combination with an effective amount of at least one (e.g., 1, 2 or 3, 1 or 2, or 1) chemotherapeutic 20 agent. Also described is a method for treating melanoma in a patient in need of such treatment, said method comprising administering to said patient an effective amount of a pharmaceutical composition comprising an effective amount of at least one (e.g., 1, 2 or 3, 1 or 2, and usually 1) compound of formula 1.0 (for example, as described in 25 any one of Embodiment Nos. 1 to 161). Also described is a method for treating melanoma in a patient in need of such treatment, said method comprising administering to said patient an effective amount of a pharmaceutical composition comprising an effective amount of at least one (e.g., 1, 2 or 3, 1 or 2, and usually 1) compound of formula 1.0 (for example, as described in 30 any one of Embodiment Nos. 1 to 161), in combination with an effective amount of at least one (e.g., 1, 2 or 3, 1 or 2, or 1) chemotherapeutic agent. Also described is a method for treating pancreatic cancer in a patient in need of such treatment, said method comprising administering to said patient an effective RECIEVED IPONZ 22 AUGUST 2011 -23- amount of at least one (e.g., 1, 2 or 3, 1 or 2, and usually 1) compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 161). Also described is a method for treating pancreatic cancer in a patient in need of such treatment, said method comprising administering to said patient an effective 5 amount of at least one (e.g., 1, 2 or 3, 1 or 2, and usually 1) compound of formula 1.0 (for example, as described in anyone of Embodiment Nos. 1 to 161), in combination with an effective amount of at least one (e.g., 1, 2 or 3, 1 or 2, or 1) chemotherapeutic agent. Also described is a method for treating pancreatic cancer in a patient in need 10 of such treatment, said method comprising administering to said patient an effective amount of a pharmaceutical composition comprising an effective amount of at least one (e.g., 1, 2 or 3, 1 or 2, and usually 1) compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 161). Also described is a method for treating pancreatic cancer in a patient in need 15 of such treatment, said method comprising administering to said patient an effective amount of a pharmaceutical composition comprising an effective amount of at least one (e.g., 1, 2 or 3, 1 or 2, and usually 1) compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 161), in combination with an effective amount of at least one (e.g., 1, 2 or 3, 1 or 2, or 1) chemotherapeutic agent. 20 Also described is a method for treating thyroid cancer in a patient in need of such treatment, said method comprising administering to said patient an effective amount of at least one (e.g., 1, 2 or 3, 1 or 2, and usually 1) compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 161). Also described is a method for treating thyroid cancer in a patient in need of 25 such treatment, said method comprising administering to said patient an effective amount of at least one (e.g., 1, 2 or 3, 1 or 2, and usually 1) compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 161), in combination with an effective amount of at least one (e.g., 1, 2 or 3, 1 or 2, or 1) chemotherapeutic agent. 30 Also described is a method for treating thyroid cancer in a patient in need of such treatment, said method comprising administering to said patient an effective amount of a pharmaceutical composition comprising an effective amount of at least one (e.g., 1, 2 or 3, 1 or 2, and usually 1) compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 161). RECIEVED IPONZ 22 AUGUST 2011 -24- Also described is a method for treating thyroid cancer in a patient in need of such treatment, said method comprising administering to said patient an effective amount of a pharmaceutical composition comprising an effective amount of at least one (e.g., 1, 2 or 3, 1 or 2, and usually 1) compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 161), in combination with an effective amount of at least one (e.g., 1, 2 or 3, 1 or 2, or 1) chemotherapeutic agent. Also described is a method for treating colorectal cancer in a patient in need of such treatment, said method comprising administering to said patient an effective amount of at least one (e.g., 1, 2 or 3, 1 or 2, and usually 1) compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 161). Also described is a method for treating colorectal cancer in a patient in need of such treatment, said method comprising administering to said patient an effective amount of at least one (e.g., 1, 2 or 3, 1 or 2, and usually 1) compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 161), in combination with an effective amount of at least one (e.g., 1, 2 or 3, 1 or 2, or 1) chemotherapeutic agent. Also described is a method for treating colorectal cancer in a patient in need of such treatment, said method comprising administering to said patient an effective amount of a pharmaceutical composition comprising an effective amount of at least one (e.g., 1, 2 or 3, 1 or 2, and usually 1) compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 161). Also described is a method for treating colorectal cancer in a patient in need of such treatment, said method comprising administering to said patient an effective amount of a pharmaceutical composition comprising an effective amount of at least one (e.g., 1, 2 or 3, 1 or 2, and usually 1) compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 161), in combination with an effective amount of at least one (e.g., 1, 2 or 3, 1 or 2, or 1) chemotherapeutic agent. Also described is a method for treating lung cancer in a patient in need of such treatment, said method comprising administering to said patient an effective amount of at least one (e.g., 1, 2 or 3, 1 or 2, and usually 1) compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 161). Also described is a method for treating lung cancer in a patient in need of such treatment, said method comprising administering to said patient an effective amount of at least one (e.g., 1, 2 or 3, 1 or 2, and usually 1) compound of formula 1.0 (for RECIEVED IPONZ 22 AUGUST 2011 -25- example, as described in any one of Embodiment Nos. 1 to 161), in combination with an effective amount of at least one (e.g., 1, 2 or 3, 1 or 2, or 1) chemotherapeutic agent. Also described is a method for treating lung cancer in a patient in need of such treatment, said method comprising administering to said patient an effective amount of a pharmaceutical composition comprising an effective amount of at least one (e.g., 1, 2 or 3, 1 or 2, and usually 1) compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 161). Also described is a method for treating lung cancer in a patient in need of such treatment, said method comprising administering to said patient an effective amount of a pharmaceutical composition comprising an effective amount of at least one (e.g., 1, 2 or 3, 1 or 2, and usually 1) compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 161), in combination with an effective amount of at least one (e.g., 1, 2 or 3, 1 or 2, or 1) chemotherapeutic agent. Also described is a method for treating breast cancer in a patient in need of such treatment, said method comprising administering to said patient an effective amount of at least one (e.g., 1, 2 or 3, 1 or 2, and usually 1) compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 161). Also described is a method for treating breast cancer in a patient in need of such treatment, said method comprising administering to said patient an effective amount of at least one (e.g., 1, 2 or 3, 1 or 2, and usually 1) compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 161), in combination with an effective amount of at least one (e.g., 1, 2 or 3, 1 or 2, or 1) chemotherapeutic agent. Also described is a method for treating breast cancer in a patient in need of such treatment, said method comprising administering to said patient an effective amount of a pharmaceutical composition comprising an effective amount of at least one (e.g., 1, 2 or 3, 1 or 2, and usually 1) compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 161). Also described is a method for treating breast cancer in a patient in need of such treatment, said method comprising administering to said patient an effective amount of a pharmaceutical composition comprising an effective amount of at least one (e.g., 1, 2 or 3, 1 or 2, and usually 1) compound of formula 1.0 (for example, as RECIEVED IPONZ 22 AUGUST 2011 -26- described in any one of Embodiment Nos. 1 to 161), in combination with an effective amount of at least one (e.g., 1, 2 or 3, 1 or 2, or 1) chemotherapeutic agent. Also described is a method for treating ovarian cancer in a patient in need of such treatment, said method comprising administering to said patient an effective amount of at least one (e.g., 1, 2 or 3, 1 or 2, and usually 1) compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 161). Also described is a method for treating ovarian cancer in a patient in need of such treatment, said method comprising administering to said patient an effective amount of at least one (e.g., 1, 2 or 3, 1 or 2, and usually 1) compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 161), in combination with an effective amount of at least one (e.g., 1, 2 or 3, 1 or 2, or 1) chemotherapeutic agent. Also described is a method for treating ovarian cancer in a patient in need of such treatment, said method comprising administering to said patient an effective amount of a pharmaceutical composition comprising an effective amount of at least one (e.g., 1, 2 or 3, 1 or 2, and usually 1) compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 161). Also described is a method for treating ovarian cancer in a patient in need of such treatment, said method comprising administering to said patient an effective amount of a pharmaceutical composition comprising an effective amount of at least one (e.g., 1, 2 or 3, 1 or 2, and usually 1) compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 161), in combination with an effective amount of at least one (e.g., 1, 2 or 3, 1 or 2, or 1) chemotherapeutic agent. Also described are methods of treating breast cancer (i.e., post-menopausal and premenopausal breast cancer, e.g., hormone-dependent breast cancer) in a patient in need of such treatment, said treatment comprising the administration of an effective amount of at least one (e.g., 1, 2 or 3, 1 or 2, and usually 1) compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 161) in combination with hormonal therapies (i.e., antihormonal agents). Also described are methods of treating breast cancer (i.e., post-menopausal and premenopausal breast cancer, e.g., hormone-dependent breast cancer) in a patient in need of such treatment, said treatment comprising the administration of an effective amount of a pharmaceutical composition comprising an effective amount of at least one (e.g., 1, 2 or 3, 1 or 2, and usually 1) compound of formula 1.0 (for RECIEVED IPONZ 22 AUGUST 2011 -27- example, as described in any one of Embodiment Nos. 1 to 161) in combination with hormonal therapies (i.e., antihormonal agents). Also described are methods of treating breast cancer (i.e., post-menopausal and premenopausal breast cancer, e.g., hormone-dependent breast cancer) in a patient in need of such treatment, said treatment comprising the administration of an effective amount of at least one (e.g., 1, 2 or 3, 1 or 2, and usually 1) compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 161) in combination with hormonal therapies (i.e., antihormonal agents), and in combination with an effective amount of at least one (e.g., 1, 2 or 3, 1 or 2, or 1) chemotherapeutic agent. Also described are methods of treating breast cancer (i.e., post-menopausal and premenopausal breast cancer, e.g., hormone-dependent breast cancer) in a patient in need of such treatment, said treatment comprising the administration of an effective amount of a pharmaceutical composition comprising an effective amount of at least one (e.g., 1, 2 or 3, 1 or 2, and usually 1) compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 161) in combination with hormonal therapies (i.e., antihormonal agents), and in combination with an effective amount of at least one (e.g., 1, 2 or 3, 1 or 2, or 1) chemotherapeutic agent. The methods of treating breast cancer described herein include the treatment of hormone-dependent metastatic and advanced breast cancer, adjuvant therapy for hormone-dependent primary and early breast cancer, the treatment of ductal carcinoma in situ, and the treatment of inflammatory breast cancer in situ. The methods of treating hormone-dependent breast cancer can also be used to prevent breast cancer in patients having a high risk of developing breast cancer. Also described are methods of preventing breast cancer (i.e., post-menopausal and premenopausal breast cancer, e.g., hormone-dependent breast cancer) in a patient in need of such treatment, said treatment comprising the administration of an effective amount of at least one (e.g., 1, 2 or 3, 1 or 2, and usually 1) compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 161) in combination with hormonal therapies (i.e., antihormonal agents). Also described are methods of preventing breast cancer (i.e., post-menopausal and premenopausal breast cancer, e.g., hormone-dependent breast cancer) in a patient in need of such treatment, said treatment comprising the administration of an effective amount of a pharmaceutical composition comprising an effective amount of RECIEVED IPONZ 22 AUGUST 2011 -28- at least one (e.g., 1, 2 or 3, 1 or 2, and usually 1) compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 161) in combination with hormonal therapies (i.e., antihormonal agents). Also described are methods of preventing breast cancer (i.e., post-menopausal and premenopausal breast cancer, e.g., hormone-dependent breast cancer) in a patient in need of such treatment, said treatment comprising the administration of an effective amount of at least one (e.g., 1, 2 or 3, 1 or 2, and usually 1) compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 161) in combination with hormonal therapies (i.e., antihormonal agents), and in combination with an effective amount of at least one (e.g., 1, 2 or 3, 1 or 2, or 1) chemotherapeutic agent. Also described are methods of preventing breast cancer (i.e., post-menopausal and premenopausal breast cancer, e.g., hormone-dependent breast cancer) in a patient in need of such treatment, said treatment comprising the administration of an effective amount of a pharmaceutical composition comprising an effective amount of at least one (e.g., 1, 2 or 3, 1 or 2, and usually 1) compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 161) in combination with hormonal therapies (i.e., antihormonal agents), and in combination with an effective amount of at least one (e.g., 1, 2 or 3, 1 or 2, or 1) chemotherapeutic agent. Also described is a method for treating brain cancer (e.g., glioma, such as glioma blastoma multiforme) in a patient in need of such treatment, said method comprising administering to said patient an effective amount of at least one (e.g., 1, 2 or 3, 1 or 2, and usually 1) compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 161). Also described is a method for treating brain cancer (e.g., glioma, such as glioma blastoma multiforme) in a patient in need of such treatment, said method comprising administering to said patient an effective amount of at least one (e.g., 1, 2 or 3, 1 or 2, and usually 1) compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 161), in combination with an effective amount of at least one (e.g., 1, 2 or 3, 1 or 2, or 1) chemotherapeutic agent. Also described is a method for treating brain cancer (e.g., glioma, such as glioma blastoma multiforme) a in a patient in need of such treatment, said method comprising administering to said patient an effective amount of a pharmaceutical composition comprising an effective amount of at least one (e.g., 1, 2 or 3, 1 or 2, and RECIEVED IPONZ 22 AUGUST 2011 -29- usually 1) compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 161). Also described is a method for treating brain cancer (e.g., glioma, such as glioma blastoma multiforme) in a patient in need of such treatment, said method 5 comprising administering to said patient an effective amount of a pharmaceutical composition comprising an effective amount of at least one (e.g., 1, 2 or 3, 1 or 2, and usually 1) compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 161), in combination with an effective amount of at least one (e.g., 1, 2 or 3, 1 or 2, or 1) chemotherapeutic agent. 10 Also described is a method for treating brain cancer (e.g., glioma, such as glioma blastoma multiforme) in a patient in need of such treatment, said method comprising administering to said patient an effective amount of at least one (e.g., 1, 2 or 3, 1 or 2, and usually 1) compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 161), in combination with an effective amount of a 15 chemotherapeutic agent wherein said chemotherapeutic agent is temozolomide. Also described is a method for treating brain cancer (e.g., glioma, such as glioma blastoma multiforme) in a patient in need of such treatment, said method comprising administering to said patient an effective amount of a pharmaceutical composition comprising an effective amount of at least one (e.g., 1, 2 or 3, 1 or 2, and 20 usually 1) compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 161), in combination with an effective amount of a chemotherapeutic agent, wherein said chemotherapeutic agent is temozolomide. Also described is a method for treating prostate cancer in a patient in need of such treatment, said method comprising administering to said patient an effective 25 amount of at least one (e.g., 1, 2 or 3, 1 or 2, and usually 1) compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 161). Also described is a method for treating prostate cancer in a patient in need of such treatment, said method comprising administering to said patient an effective amount of at least one (e.g., 1, 2 or 3, 1 or 2, and usually 1) compound of formula 1.0 30 (for example, as described in any one of Embodiment Nos. 1 to 161), in combination with an effective amount of at least one (e.g., 1, 2 or 3, 1 or 2, or 1) chemotherapeutic agent. Also described is a method for treating prostate cancer in a patient in need of such treatment, said method comprising administering to said patient an effective RECIEVED IPONZ 22 AUGUST 2011 -30 - amount of a pharmaceutical composition comprising an effective amount of at least one (e.g., 1, 2 or 3, 1 or 2, and usually 1) compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 161). Also described is a method for treating prostate cancer in a patient in need of such treatment, said method comprising administering to said patient an effective amount of a pharmaceutical composition comprising an effective amount of at least one (e.g., 1, 2 or 3, 1 or 2, and usually 1) compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 161), in combination with an effective amount of at least one (e.g., 1, 2 or 3, 1 or 2, or 1) chemotherapeutic agent. Also described is a method for treating myelodysplastic syndrome in a patient in need of such treatment, said method comprising administering to said patient an effective amount of at least one (e.g., 1, 2 or 3, 1 or 2, and usually 1) compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 161). Also described is a method for treating myelodysplastic syndrome in a patient in need of such treatment, said method comprising administering to said patient an effective amount of at least one (e.g., 1, 2 or 3, 1 or 2, and usually 1) compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 161), in combination with an effective amount of at least one (e.g., 1, 2 or 3, 1 or 2, or 1) chemotherapeutic agent. Also described is a method for treating myelodysplastic syndrome in a patient in need of such treatment, said method comprising administering to said patient an effective amount of a pharmaceutical composition comprising an effective amount of at least one (e.g., 1, 2 or 3, 1 or 2, and usually 1) compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 161). Also described is a method for treating myelodysplastic syndrome in a patient in need of such treatment, said method comprising administering to said patient an effective amount of a pharmaceutical composition comprising an effective amount of at least one (e.g., 1, 2 or 3, 1 or 2, and usually 1) compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 161), in combination with an effective amount of at least one (e.g., 1, 2 or 3, 1 or 2, or 1) chemotherapeutic agent. Also described is a method for treating myeloid leukemias in a patient in need of such treatment, said method comprising administering to said patient an effective RECIEVED IPONZ 22 AUGUST 2011 -31 - amount of at least one (e.g., 1, 2 or 3, 1 or 2, and usually 1) compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 161). Also described is a method for treating myeloid leukemias in a patient in need of such treatment, said method comprising administering to said patient an effective amount of at least one (e.g., 1, 2 or 3, 1 or 2, and usually 1) compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 161), in combination with an effective amount of at least one (e.g., 1, 2 or 3, 1 or 2, or 1) chemotherapeutic agent. Also described is a method for treating myeloid leukemias in a patient in need of such treatment, said method comprising administering to said patient an effective amount of a pharmaceutical composition comprising an effective amount of at least one (e.g., 1, 2 or 3, 1 or 2, and usually 1) compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 161). Also described is a method for treating myeloid leukemias in a patient in need of such treatment, said method comprising administering to said patient an effective amount of a pharmaceutical composition comprising an effective amount of at least one (e.g., 1, 2 or 3, 1 or 2, and usually 1) compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 161), in combination with an effective amount of at least one (e.g., 1, 2 or 3, 1 or 2, or 1) chemotherapeutic agent. Also described is a method for treating acute myelogenous leukemia (AML) in a patient in need of such treatment, said method comprising administering to said patient an effective amount of at least one (e.g., 1, 2 or 3, 1 or 2, and usually 1) compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 161). Also described is a method for treating acute myelogenous leukemia (AML) in a patient in need of such treatment, said method comprising administering to said patient an effective amount of at least one (e.g., 1, 2 or 3, 1 or 2, and usually 1) compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 161), in combination with an effective amount of at least one (e.g., 1, 2 or 3, 1 or 2, or 1) chemotherapeutic agent. Also described is a method for treating acute myelogenous leukemia (AML)in a patient in need of such treatment, said method comprising administering to said patient an effective amount of a pharmaceutical composition comprising an effective RECIEVED IPONZ 22 AUGUST 2011 -32- amount of at least one (e.g., 1, 2 or 3, 1 or 2, and usually 1) compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 161). Also described is a method for treating acute myelogenous leukemia (AML)in a patient in need of such treatment, said method comprising administering to said patient an effective amount of a pharmaceutical composition comprising an effective amount of at least one (e.g., 1, 2 or 3, 1 or 2, and usually 1) compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 161), in combination with an effective amount of at least one (e.g., 1, 2 or 3, 1 or 2, or 1) chemotherapeutic agent. Also described is a method for treating chronic myelomonocytic leukemia (CMML) in a patient in need of such treatment, said method comprising administering to said patient an effective amount of at least one (e.g., 1, 2 or 3, 1 or 2, and usually 1) compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 161). Also described is a method for treating chronic myelomonocytic leukemia (CMML) in a patient in need of such treatment, said method comprising administering to said patient an effective amount of at least one (e.g., 1, 2 or 3, 1 or 2, and usually 1) compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 161), in combination with an effective amount of at least one (e.g., 1, 2 or 3, 1 or 2, or 1) chemotherapeutic agent. Also described is a method for treating chronic myelomonocytic leukemia (CMML) in a patient in need of such treatment, said method comprising administering to said patient an effective amount of a pharmaceutical composition comprising an effective amount of at least one (e.g., 1, 2 or 3, 1 or 2, and usually 1) compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 161). Also described is a method for treating chronic myelomonocytic leukemia (CMML) in a patient in need of such treatment, said method comprising administering to said patient an effective amount of a pharmaceutical composition comprising an effective amount of at least one (e.g., 1, 2 or 3, 1 or 2, and usually 1) compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 161), in combination with an effective amount of at least one (e.g., 1, 2 or 3, 1 or 2, or 1) chemotherapeutic agent. Also described is a method for treating chronic myelogenous leukemia (chronic myeloid leukemia, CML) in a patient in need of such treatment, said method RECIEVED IPONZ 22 AUGUST 2011 -33- comprising administering to said patient an effective amount of at least one (e.g., 1, 2 or 3, 1 or 2, and usually 1) compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 161). Also described is a method for treating chronic myelogenous leukemia (chronic myeloid leukemia, CML) in a patient in need of such treatment, said method comprising administering to said patient an effective amount of at least one (e.g., 1, 2 or 3, 1 or 2, and usually 1) compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 161), in combination with an effective amount of at least one (e.g., 1, 2 or 3, 1 or 2, or 1) chemotherapeutic agent. Also described is a method for treating chronic myelogenous leukemia (chronic myeloid leukemia, CML) in a patient in need of such treatment, said method comprising administering to said patient an effective amount of a pharmaceutical composition comprising an effective amount of at least one (e.g., 1, 2 or 3, 1 or 2, and usually 1) compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 161). Also described is a method for treating chronic myelogenous leukemia (chronic myeloid leukemia, CML) in a patient in need of such treatment, said method comprising administering to said patient an effective amount of a pharmaceutical composition comprising an effective amount of at least one (e.g., 1, 2 or 3, 1 or 2, and usually 1) compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 161), in combination with an effective amount of at least one (e.g., 1, 2 or 3, 1 or 2, or 1) chemotherapeutic agent. Also described is a method for treating myeloid leukemias in a patient in need of such treatment, said method comprising administering to said patient an effective amount of at least one (e.g., 1, 2 or 3, 1 or 2, and usually 1) compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 161). Also described is a method for treating myeloid leukemias in a patient in need of such treatment, said method comprising administering to said patient an effective amount of at least one (e.g., 1, 2 or 3, 1 or 2, and usually 1) compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 161), in combination with an effective amount of at least one (e.g., 1, 2 or 3, 1 or 2, or 1) chemotherapeutic agent. Also described is a method for treating myeloid leukemias in a patient in need of such treatment, said method comprising administering to said patient an effective RECIEVED IPONZ 22 AUGUST 2011 -34- amount of a pharmaceutical composition comprising an effective amount of at least one (e.g., 1, 2 or 3, 1 or 2, and usually 1) compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 161). Also described is a method for treating myeloid leukemias in a patient in need of such treatment, said method comprising administering to said patient an effective amount of a pharmaceutical composition comprising an effective amount of at least one (e.g., 1, 2 or 3, 1 or 2, and usually 1) compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 161), in combination with an effective amount of at least one (e.g., 1, 2 or 3, 1 or 2, or 1) chemotherapeutic agent. Also described is a method for treating bladder cancer in a patient in need of such treatment, said method comprising administering to said patient an effective amount of at least one (e.g., 1, 2 or 3, 1 or 2, and usually 1) compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 161). Also described is a method for treating bladder cancer in a patient in need of such treatment, said method comprising administering to said patient an effective amount of at least one (e.g., 1, 2 or 3, 1 or 2, and usually 1) compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 161), in combination with an effective amount of at least one (e.g., 1, 2 or 3, 1 or 2, or 1) chemotherapeutic agent. Also described is a method for treating bladder cancer in a patient in need of such treatment, said method comprising administering to said patient an effective amount of a pharmaceutical composition comprising an effective amount of at least one (e.g., 1, 2 or 3, 1 or 2, and usually 1) compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 161). Also described is a method for treating bladder cancer in a patient in need of such treatment, said method comprising administering to said patient an effective amount of a pharmaceutical composition comprising an effective amount of at least one (e.g., 1, 2 or 3, 1 or 2, and usually 1) compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 161), in combination with an effective amount of at least one (e.g., 1, 2 or 3, 1 or 2, or 1) chemotherapeutic agent. Also described is a method for treating non-Hodgkin's lymphoma in a patient in need of such treatment, said method comprising administering to said patient an effective amount of at least one (e.g., 1, 2 or 3, 1 or 2, and usually 1) compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 161). RECIEVED IPONZ 22 AUGUST 2011 -35- Also described is a method for treating non-Hodgkin's lymphoma in a patient in need of such treatment, said method comprising administering to said patient an effective amount of at least one (e.g., 1, 2 or 3, 1 or 2, and usually 1) compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 161), in combination with an effective amount of at least one (e.g., 1, 2 or 3, 1 or 2, or 1) chemotherapeutic agent. Also described is a method for treating non-Hodgkin's lymphoma in a patient in need of such treatment, said method comprising administering to said patient an effective amount of a pharmaceutical composition comprising an effective amount of at least one (e.g., 1, 2 or 3, 1 or 2, and usually 1) compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 161). Also described is a method for treating non-Hodgkin's lymphoma in a patient in need of such treatment, said method comprising administering to said patient an effective amount of a pharmaceutical composition comprising an effective amount of at least one (e.g., 1, 2 or 3, 1 or 2, and usually 1) compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 161), in combination with an effective amount of at least one (e.g., 1, 2 or 3, 1 or 2, or 1) chemotherapeutic agent. Also described is a method for treating multiple myeloma in a patient in need of such treatment, said method comprising administering to said patient an effective amount of at least one (e.g., 1, 2 or 3, 1 or 2, and usually 1) compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 161). Also described is a method for treating multiple myeloma in a patient in need of such treatment, said method comprising administering to said patient an effective amount of at least one (e.g., 1, 2 or 3, 1 or 2, and usually 1) compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 161), in combination with an effective amount of at least one (e.g., 1, 2 or 3, 1 or 2, or 1) chemotherapeutic agent. Also described is a method for treating multiple myeloma in a patient in need of such treatment, said method comprising administering to said patient an effective amount of a pharmaceutical composition comprising an effective amount of at least one (e.g., 1, 2 or 3, 1 or 2, and usually 1) compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 161). RECIEVED IPONZ 22 AUGUST 2011 -36- Also described is a method for treating multiple myeloma in a patient in need of such treatment, said method comprising administering to said patient an effective amount of a pharmaceutical composition comprising an effective amount of at least one (e.g., 1, 2 or 3, 1 or 2, and usually 1) compound of formula 1.0 (for example, as 5 described in any one of Embodiment Nos. 1 to 161), in combination with an effective amount of at least one (e.g., 1, 2 or 3, 1 or 2, or 1) chemotherapeutic agent. In the methods described the compounds of this invention can be administered concurrently or sequentially (i.e., consecutively) with the chemotherapeutic agents or the signal transduction inhibitor. 10 The methods of treating cancers described herein can optionally include the administration of an effective amount of radiation (i.e., the methods of treating cancers described herein optionally include the administration of radiation therapy). DETAILED DESCRIPTION OF THE INVENTION 15 As described herein, unless otherwise indicated, the use of a drug or compound in a specified period is per treatment cycle. For example, once a day means once per day of each day of the treatment cycle. Twice a day means twice per day each day of the treatment cycle. Once a week means one time per week during the treatment cycle. Once every three weeks means once per three weeks 20 during the treatment cycle. The following abbreviations have the following meanings unless defined otherwise: ACN Acetonitrile AcOH Acetic acid 25 DAST (diethylamino)sulfur trifluoride DCC Dicyclohexylcarbodiimide DCU Dicyclohexylurea DCM Dichloromethane DIAD Diisopropylazodicarboxylate 30 DIEA Diisopropylethylamine DMAP 4-Dimethylaminopyridine DME Dimethoxyethane DMF Dimethylformamide DMFDMA N,N-Dimethylformamide dimethylaceta 35 DMSO Dimethyl sulfoxide RECIEVED IPONZ 22 AUGUST 2011 -37- DTT Dithiothreitol EDCI 1 -(3-dimethylamino-propyl)-3-ethylcarbodiimide hydrochloride EtOAc Ethyl acetate EtOH Ethanol 5 HATU N,N,N',N,-Tetramethyl-0-(7-Azabenzotriazol-1-yl)Uronium hexafluorophosphate Hex hexanes HOBt 1-Hydroxylbenzotriazole HPLC High pressure liquid chromatography 10 LCMS Liquid chromatography mass spectrometry LDA Lithium diisopropylamide mCPBA mefa-Chloroperoxybenzoic acid MeOH Methanol MTT (3-[4,5-dimethyl-thiazol-2-yl]-2,5-diphenyltetrazolium bromide, 15 Thiazolyl blue) NMR Nuclear magnetic resonance PFP Pentafluorophenol PMB p-methoxybenzyl Pyr Pyridine 20 RT Room temperature SEMCI 2-(Trimethylsily)ethoxy methyl chloride TEA Triethylamine Tr Triphenyl methane TrCI Triphenyl methane chloride 25 TFA Trifluoroacetic acid THF Tetrahydrofuran TLC Thin layer chromatography TMS Trimethylsilyl 30 As used herein, unless otherwise specified, the following terms have the following meanings: "anti-cancer agent" means a drug (medicament or pharmaceutically active ingredient) for treating cancer; "antineoplastic agent" means a drug (medicament or pharmaceutically 35 active ingredient) for treating cancer (i.e., a chemotherapeutic agent); RECIEVED IPONZ 22 AUGUST 2011 -38 - "at least one", as used in reference to the number of compounds of this invention means for example 1-6, generally 1-4, more generally 1, 2 or 3, and usually one or two, and more usually one; "at least one", as used in reference to the number of chemotherapeutic agents used, means for example 1-6, generally 1-4, more generally 1, 2 or 3, and usually one or two, or one; "chemotherapeutic agent" means a drug (medicament or pharmaceutically active ingredient) for treating cancer (i.e., and antineeoplastic agent); "compound" with reference to the antineoplastic agents, includes the agents that are antibodies; "concurrently" means (1) simultaneously in time (e.g., at the same time); or (2) at different times during the course of a common treatment schedule; "consecutively" means one following the other; "different" as used in the phrase "different antineoplastic agents" means that the agents are not the same compound or structure; preferably, "different" as used in the phrase "different antineoplastic agents" means not from the same class of antineoplastic agents; for example, one antineoplastic agent is a taxane, and another antineoplastic agent is a platinum coordinator compound; "effective amount" or "therapeutically effective amount" is meant to describe an amount of compound or a composition of the present invention, or an amount of radiation, effective in treating or inhibiting the diseases or conditions described herein, and thus producing the desired therapeutic, ameliorative, inhibitory or preventative effect; thus, for example, in the methods of treating cancer described herein and uses of the invention "effective amount" (or "therapeutically effective amount") means, for example, the amount of the compound (or drug), or radiation, that results in: (a) the reduction, alleviation or disappearance of one or more symptoms caused by the cancer, (b) the reduction of tumor size, (c) the elimination of the tumor, and/or (d) long-term disease stabilization (growth arrest) of the tumor; for example, in the treatment of lung cancer (e.g., non small cell lung cancer) a therapeutically effective amount is that amount that alleviates or eliminates cough, shortness of breath and/or pain; also, for example, an effective amount, or a therapeutically effective amount of the ERK inhibitor (i.e., a compound of this invention) is that amount which results in the reduction in ERK (ERK1 and/or ERK2) activity and phosphorylation; the reduction in ERK activity may be determined by the RECIEVED IPONZ 22 AUGUST 2011 -39- analysis of pharmacodynamic markers such as phosphorylated RSK1,2 and phosphorylated ERK1,2, using techniques well known in the art; "Ex" in the tables represents "Example"; "one or more" has the same meaning as "at least one"; "patient" means an animal, such as a mammal (e.g., a human being, and preferably a human being); "prodrug" means compounds that are rapidly transformed, for example, by hydrolysis in blood, in vivo to the parent compound, i.e., to the compounds of formula 1.0 or to a salt and/or to a solvate thereof; a thorough discussion is provided in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the A.C.S. Symposium Series, and in Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated herein by reference; the scope of this invention includes Prodrugs of the novel compounds of this invention; sequentially-represents (1) administration of one component .of the method described or use of the invention of ((a) compound of the invention, or (b) chemotherapeutic agent, signal transduction inhibitor and/or radiation therapy) followed by administration of the other component or components; after adminsitration of one component, the next component can be administered substantially immediately after the first component, or the next component can be administered after an effective time period after the first component; the effective time period is the amount of time given for realization of maximum benefit from the administration of the first component; and "solvate" means a physical association of a compound of this invention with one or more solvent molecules; this physical association involves varying degrees of ionic and covalent bonding, including hydrogen bonding; in certain instances the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid; "solvate" encompasses both solution-phase and isolatable solvates; non-limiting examples of suitable solvates include ethanolates, methanolates, and the like; "hydrate" is a solvate wherein the solvent molecule is H2O. As used herein, unless otherwise specified, the following terms have the following meanings, and unless otherwise specified, the definitions of each term (i.e., moiety or substituent) apply when that term is used individually or as a component of RECIEVED IPONZ 22 AUGUST 2011 -40- another term (e.g., the definition of aryl is the same for aryl and for the aryl portion of arylalkyl, alkylaryl, arylalkynyl, and the like): "acyl" means an H-C(O)-, alkyl-C(O)-, alkenyl-C(O)-, Alkynyl-C(O)-, cycloalkyl-C(O)-, cycloalkenyl-C(O)-, or cycloalkynyl-C(O)- group in which the various 5 groups are as defined below (and as defined below, the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl and cycloalkynyl moieties can be substituted); the bond to the parent moiety is through the carbonyl; preferred acyls contain a lower alkyl; Non-limiting examples of suitable acyl groups include formyl, acetyl, propanoyl, 2-methylpropanoyl, butanoyl and cyclohexanoyl; 10 "alkenyl" means an aliphatic hydrocarbon group (chain) comprising at least one carbon to carbon double bond, wherein the chain can be straight or branched, and wherein said group comprises about 2 to about 15 carbon atoms; Preferred alkenyl groups comprise about 2 to about 12 carbon atoms in the chain; and more preferably about 2 to about 6 carbon atoms in the chain; branched means 15 that one or more lower alkyl groups, such as methyl, ethyl or propyl, or alkenyl_groups are attached to a linear alkenyl chain; "lower alkenyl" means an alkenyl group comprising about 2 to about 6 carbon atoms in the chain, and the chain can be straight or branched; the term "substituted alkenyl" means that the alkenyl group is substituted by one or more independently selected substituents, and each substituent 20 is independently selected from the group consisting of: halo, alkyl, aryl, cycloalkyl, cyano, alkoxy and -S(alkyl); non-limiting examples of suitable alkenyl groups include ethenyl, propenyl, n-butenyl, 3-methylbut-2-enyl, n-pentenyl, octenyl and decenyl; "alkoxy" means an alkyl-O- group (i.e., the bond to the parent moiety is through the ether oxygen) in which the alkyl group is unsubstituted or substituted as 25 described below; non-limiting examples of suitable alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy and heptoxy; "alkoxycarbonyl" means an alkyl-O-CO- group (i.e., the bond to the parent moiety is through the carbonyl) wherein the alkyl group is unsubstituted or substituted as previously defined; non-limiting examples of suitable alkoxycarbonyl groups include 30 methoxycarbonyl and ethoxycarbonyl; "alkyl" (including the alkyl portions of other moieties, such as trifluoroalkyl and alkyloxy) means an aliphatic hydrocarbon group (chain) that can be straight or branched wherein said group comprises about 1 to about 20 carbon atoms in the chain; preferred alkyl groups comprise about 1 to about 12 carbon atoms in the chain; RECIEVED IPONZ 22 AUGUST 2011 -41 - more preferred alkyl groups comprise about 1 to about 6 carbon atoms in the chain; branched means that one or more lower alkyl groups, such as methyl, ethyl or propyl, are attached to a linear alkyl chain; "lower alkyl" means a group comprising about 1 to about 6 carbon atoms in the chain, and said chain can be straight or branched; the term "substituted alkyl" means that the alkyl group is substituted by one or more independently selected substituents, and wherein each substituent is independently selected from the group consisting of; halo, aryl, cycloalkyl, cyano, hydroxy, alkoxy, alkylthio, amino, -NH(alkyl), -NH(cycloalkyl), -N(alkyl)2, carboxy, -C(0)0-alkyl and -S(alkyl); non-limiting examples of suitable alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, n-pentyl, heptyl, nonyl, decyl, fluoromethyl, trifluoromethyl and cyclopropylmethyl; "alkylaryl" (or alkaryl) means an alkyl-aryl- group (i.e., the bond to the parent moiety is through the aryl group) wherein the alkyl group is unsubstituted or substituted as defined above, and the aryl group is unsubstituted or substituted as defined below; preferred alkylaryls comprise a lower alkyl group; non-limiting examples of suitable alkylaryl groups include o-tolyl, p-tolyl and xylyl; "alkylheteroaryl" means an alkyl-heteroaryl- group (i.e., the bond to the parent moiety is through the heteroaryl group) wherein the alkyl is unsubstituted or substituted as defined above and the heteroaryl group is unsubstituted or substituted as defined below; "alkylsulfinyl" means an alkyl-S(O)- group (i.e., the bond to the parent moiety is through the sulfinyl) wherein the alkyl group is unsubstituted or substituted as previously defined; preferred groups are those in which the alkyl group is lower alkyl; "alkylsulfonyl" means an alkyl-S(02)- group (i.e., the bond to the parent moiety is through the sulfonyl) wherein the alkyl group is unsubstituted or substituted as previously defined; preferred groups are those in which the alkyl group is lower alkyl; "alkylthio" means an alkyl-S- group (i.e., the bond to the parent moiety is through the sulfur) wherein the alkyl group is unsubstituted or substituted as previously described; non-limiting examples of suitable alkylthio groups include methylthio, ethylthio, i-propylthio and heptylthio; "alkynyl" means an aliphatic hydrocarbon group (chain) comprising at least one carbon to carbon triple bond, wherein the chain can be straight or branched, RECIEVED IPONZ 22 AUGUST 2011 -42- and wherein the group comprises about 2 to about 15 carbon atoms in the; preferred alkynyl groups comprise about 2 to about 12 carbon atoms in the chain; and more preferably about 2 to about 4 carbon atoms in the chain; Branched means that one or more lower alkyl groups, such as methyl, ethyl or propyl, are attached to a linear 5 alkynyl chain; "lower alkynyl" means an alkynyl group comprising about 2 to about 6 carbon atoms in the chain, and the chain can be straight or branched; non-limiting examples of suitable alkynyl groups include ethynyl, propynyl, 2-butynyl, 3-methylbutynyl, n-pentynyl, and decynyl; the term "substituted alkynyl" means that the alkynyl group is substituted by one or more independently selected, and each 10 substituent is independently selected from the group consisting of alkyl; aryl and cycloalkyl; "amino means a -NH2 group; "aralkenyl" (or arylalkenyl) means an aryl-alkenyl- group (i.e., the bond to the parent moiety is through the alkenyl group) wherein the aryl group is unsubstituted 15 or substituted as defined below, and the alkenyl group is unsubstituted or substituted as defined above; preferred aralkenyls contain a lower alkenyl group; non-limiting examples of suitable aralkenyl groups include 2-phenethenyl and 2-naphthylethenyl; "aralkyl" (or arylalkyl) means an aryl-alkyl- group (i.e., the bond to the parent moiety is through the alkyl group) wherein the aryl is unsubstituted or 20 substituted as defined below and the alkyl is unsubstituted or substituted as defined above; preferred aralkyls comprise a lower alkyl group; non-limiting examples of suitable aralkyl groups include benzyl, 2-phenethyl and naphthalenylmethyl; "aralkyloxy" (or arylalkyloxy) means an aralkyl-O- group (i.e., the bond to the parent moiety is through the ether oxygen) wherein the aralkyl group is 25 unsubstituted or substituted as previously described; non-limiting examples of suitable aralkyloxy groups include benzyloxy and 1- or 2-naphthalenemethoxy; "aralkoxycarbonyl" means an aralkyl-O-C(O)- group (i.e., the bond to the parent moiety is through the carbonyl) wherein the aralkyl group is unsubstituted or substituted as previously defined; a non-limiting example of a suitable 30 aralkoxycarbonyl group is benzyloxycarbonyl; "aralkylthio" means an aralkyl-S- group (i.e., the bond to the parent moiety is through the sulfur) wherein the aralkyl group is unsubstituted or substituted as previously described; a non-limiting example of a suitable aralkylthio group is benzylthio; RECIEVED IPONZ 22 AUGUST 2011 -43- "aroyl" means an aryl-C(O)- group (i.e., the bond to the parent moiety is through the carbonyl) wherein the aryl group is unsubstituted or substituted as defined below; non-limiting examples of suitable groups include benzoyl and 1- and 2-naphthoyl; "aryl" (sometimes abbreviated "ar") means an aromatic monocyclic or multicyclic ring system comprising about 6 to about 14 carbon atoms, preferably about 6 to about 10 carbon atoms; the aryl group can be optionally substituted with one or more independently selected "ring system substituents" (defined below). Non-limiting examples of suitable aryl groups include phenyl and naphthyl; "arylalkynyl" means an aryl-alkynyl- group (i.e., the bond to the parent moiety is through the alkynyl group) wherein the aryl group is unsubstituted or substituted as defined above, and the alkynyl group is unsubstituted or substitutedas defined above; "arylaminoheteroaryl" means an aryl-amino-heteroaryl group (i.e., the bond to the parent moiety is through the heteroaryl. group) wherein the aryl group is unsubstituted or substituted as defined above, the amino group is as defined above (i.e., a -NH- here), and the heteroaryl group is unsubstituted or substituted as defined below; "arylheteroaryl" means an aryl-heteroarylgroup-(i.e., the bond to the parent moiety is through the heteroaryl group) wherein the aryl group is unsubstituted or substituted as defined above, and the heteroaryl group is unsubstituted or substituted as defined below; "aryloxy" means an aryl-O- group (i.e., the bond to the parent moiety is through the ether oxygen) wherein the aryl group is unsubstituted or substituted as defined above; non-limiting examples of suitable aryloxy groups include phenoxy and naphthoxy; "aryloxycarbonyl" means an aryl-O-C(O)- group (i.e., the bond to the parent moiety is through the carbonyl) wherein the aryl group is unsubstituted or substituted as previously defined; non-limiting examples of suitable aryloxycarbonyl groups include phenoxycarbonyl and naphthoxycarbonyl; "arylsulfinyl" means an aryl-S(O)- group (i.e., the bond to the parent moiety is through the sulfinyl) wherein aryl is unsubstituted or substituted as previously defined; RECIEVED IPONZ 22 AUGUST 2011 -44- "arylsulfonyl" means an aryl-S(02)- group (i.e., the bond to the parent moiety is through the sulfonyl) wherein aryl is unsubstituted or substituted as previously defined; "arylthio" means an aryl-S- group (i.e., the bond to the parent moiety is through the sulfur) wherein the aryl group is unsubstituted or substituted as previously described; non-limiting examples of suitable arylthio groups include phenylthio and naphthylthio; "cycloalkenyl" means a non-aromatic mono or multicyclic ring system comprising about 3 to about 10 carbon atoms, preferably about 5 to about 10 carbon atoms that contains at least one carbon-carbon double bond; preferred cycloalkenyl rings contain about 5 to about 7 ring atoms; the cycloalkenyl can be optionally substituted with one or more independently selected "ring system substituents" (defined below); Non-limiting examples of suitable monocyclic cycloalkenyls include cyclopentenyl, cyclohexenyl, cycloheptenyl, and the like; a non-limiting example of a suitable multicyclic cycloalkenyl is norbornylenyl; "cycloalkyl" means a non-aromatic mono- or multicyclic ring system comprising about 3 to about 7 carbon atoms, preferably about 3 to about 6 carbon atoms; the cycloalkyl can be optionally substituted with one or more independently selected "ring system substituents" (defined below); non-limiting examples of suitable monocyclic cycloalkyls include cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl and the like; non-limiting examples of suitable multicyclic cycloalkyls include 1-decalin, norbornyl, adamantyl and the like; "cycloalkylalkyl" means a cycloalkyl-alkyl-group (i.e., the bond to the parent moiety is through the alkyl group) wherein the cycloalkyl moiety is unsubstituted or substituted as defined above, and the alkyl moiety is unsubstituted or substituted as defined above; "halo" means fluoro, chloro, bromo, or iodo groups; preferred halos are fluoro, chloro or bromo, and more preferred are fluoro and chloro; "halogen" means fluorine, chlorine, bromine, or iodine; preferred halogens are fluorine, chlorine and bromine; "haloalkyl" means an alkyl, as defined above, wherein one or more hydrogen atoms on the alkyl is replaced by a halo group, as defined above; "heteroaralkenyl" means a heteroaryl-alkenyl- group (i.e., the bond to the parent moiety is through the alkenyl group) wherein the heteroaryl group is RECIEVED IPONZ 22 AUGUST 2011 -45- unsubstituted or substituted as defined below, and the alkenyl group is unsubstituted or substituted as defined above; "heteroaralkyl" (or heteroarylalkyl) means a heteroaryl-alkyl- group (i.e., the bond to the parent moiety is through the alkyl group) in which the heteroaryl is 5 unsubstituted or substituted as defined below, and the alkyl group is unsubstituted or substituted as defined above; preferred heteroaralkyls comprise an alkyl group that is a lower alkyl group; non-limiting examples of suitable aralkyl groups include pyridylmethyl, 2-(furan-3-yl)ethyl and quinolin-3-ylmethyl; "heteroaralkylthio" means a heteroaralkyl-S- group wherein the 10 heteroaralkyl group is unsubstituted or substituted as defined above; "heteroaryl" means an aromatic monocyclic or multicyclic ring system comprising about 5 to about 14 ring atoms, preferably about 5 to about 10 ring atoms, in which one or more of the ring atoms is an element other than carbon, for example nitrogen, oxygen or sulfur, alone or in combination; preferred heteroaryls comprise 15 about 5 to about 6 ring atoms; the "heteroaryl" can be optionally substituted by one or more independently selected "ring system substituents" (defined below); the prefix aza, oxa or thia before the heteroaryl root name means that at least a nitrogen, oxygen or sulfur atom, respectively, is present as a ring atom; a nitrogen atom of a heteroaryl can be optionally oxidized to the corresponding N-oxide; non-limiting 20 examples of suitable heteroaryls include pyridyl, pyrazinyl, furanyl, thienyl, pyrimidinyl, isoxazolyl, isothiazolyl, oxazolyl, thiazolyl, pyrazolyl, furazanyl, pyrrolyl, pyrazolyl, triazolyl, 1,2,4-thiadiazolyl, pyrazinyl, pyridazinyl, quinoxalinyl, phthalazinyl, imidazo[1,2-a]pyridinyl, imidazo[2,1-b]thiazolyl, benzofurazanyl, indolyl, azaindolyl, benzimidazolyl, benzothienyl, quinolinyl, imidazolyl, thienopyridyl, quinazolinyl, 25 thienopyrimidyl, pyrrolopyridyl, imidazopyridyl, isoquinolinyl, benzoazaindolyl, 1,2,4-triazinyl, benzothiazolyl and the like; "heteroarylalkynyl" (or heteroaralkynyl) means a heteroaryl-alkynyl- group (i.e., the bond to the parent moiety is through the alkynyl group) wherein the heteroaryl group is unsubstituted or substituted as defined above, and the alkynyl 30 group is unsubstituted or substituted as defined above; "heteroarylaryl" (or heteroararyl) means a heteroaryl-aryl- group (i.e., the bond to the parent moiety is through the aryl group) wherein the heteroaryl group is unsubstituted or substituted as defined above, and the aryl group is unsubstituted or substituted as defined above; RECIEVED IPONZ 22 AUGUST 2011 -46- "heteroarylheteroarylaryl" means a heteroaryl-heteroaryl- group (i.e., the bond to the parent moiety is through the last heteroaryl group) wherein each heteroaryl group is independently unsubstituted or substituted as defined above; "heteroarylsulfinyl" means a heteroaryl-SO- group wherein the heteroaryl group is unsubstituted or substituted as defined above; "heteroarylsulfonyl" means a heteroaryl-S02- group wherein the heteroaryl group is unsubstituted or substituted as defined above; "heteroarylthio" means a heteroaryl-S- group wherein the heteroaryl group is unsubstituted or substituted as defined above; "heterocyclenyl" (or heterocycloalkenyl) means a non-aromatic monocyclic or multicyclic ring system comprising about 3 to about 10 ring atoms, preferably about 5 to about 10 ring atoms, in which one or more of the atoms in the ring system is an element other than carbon (for example one or more heteroatoms independently selected from the group consisting of nitrogen, oxygen and sulfur atom), and which contains at least one carbon-carbon double bond or carbon-nitrogen double bond; there are no adjacent oxygen and/or sulfur atoms present in the ring system; Preferred heterocyclenyl rings contain about 5 to about 6 ring atoms; the prefix aza, oxa or thia before the heterocyclenyl root name means that at least a nitrogen, oxygen or sulfur atom, respectively, is present as a ring atom; the heterocyclenyl can be optionally substituted by one or more independently selected "Ring system substituents" (defined below); the nitrogen or sulfur atom of the heterocyclenyl can be optionally oxidized to the corresponding N-oxide, S-oxide or S,S-dioxide; non-limiting examples of suitable monocyclic azaheterocyclenyl groups include 1,2,3,4-tetrahydropyridine, 1,2-dihydropyridyl, 1,4-dihydropyridyl, 1,2,3,6-tetrahydropyridine, 1,4,5,6-tetrahydropyrimidine, 2-pyrrolinyl, 3-pyrrolinyl, 2-imidazolinyl, 2-pyrazolinyl, and the like; Non-limiting examples of suitable oxaheterocyclenyl groups include 3,4-dihydro-2H-pyran, dihydrofuranyl, fluorodihydrofuranyl, and the like; A non-limiting example of a suitable multicyclic oxaheterocyclenyl group is 7-oxabicyclo[2.2.1]heptenyl; non-limiting examples of suitable monocyclic thiaheterocyclenyl rings include dihydrothiophenyl, dihydrothiopyranyl, and the like; "heterocycloalkylalkyl" (or heterocyclylalkyl) means a heterocycloalkylalkyl- group (i.e., the bond to the parent moiety is through the alkyl group) wherein the heterocycloalkyl group (i.e., the heterocyclyl group) is unsubstituted or substituted as defined below, and the alkyl group is unsubstituted or substituted as defined above; RECIEVED IPONZ 22 AUGUST 2011 -47- "heterocyclyl" (or heterocycloalkyl) means a non-aromatic saturated monocyclic or multicyclic ring system comprising about 3 to about 10 ring atoms, preferably about 5 to about 10 ring atoms, in which one or more of the atoms in the ring system is an element other than carbon, for example nitrogen, oxygen or sulfur, 5 alone or in combination; there are no adjacent oxygen and/or sulfur atoms present in the ring system; preferred heterocyclyls contain about 5 to about 6 ring atoms; the prefix aza, oxa or thia before the heterocyclyl root name means that at least a nitrogen, oxygen or sulfur atom respectively is present as a ring atom; the heterocyclyl can be optionally substituted by one or more independently selected "ring system 10 substituents" (defined below); the nitrogen or sulfur atom of the heterocyclyl can be optionally oxidized to the corresponding N-oxide, S-oxide or S,S-dioxide; non-limiting examples of suitable monocyclic heterocyclyl rings include piperidyl, pyrrolidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, 1,3-dioxolanyl, 1,4-dioxanyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, and the like; 15 "hydroxyalkyl" means a HO-alkyl- group wherein the alkyl group is substituted or unsubstituted as defined above; preferred hydroxyalkyls comprise a lower alkyl; Non-limiting examples of suitable hydroxyalkyl groups include hydroxymethyl and 2-hydroxyethyl; and "ring system substituent" means a substituent attached to an aromatic or 20 non-aromatic ring system that, for example, replaces an available hydrogen on the ring system; ring system substituents are each independently selected from the group consisting of; alkyl, aryl, heteroaryl, aralkyl, alkylaryl, aralkenyl, heteroaralkyl, alkylheteroaryl, heteroaralkenyl, hydroxy, hydroxyalkyl, alkoxy, aryloxy, aralkoxy, acyl, aroyl, halo, nitro, cyano, carboxy, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, 25 alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, alkylsulfinyl, arylsulfinyl, heteroarylsulfinyl, alkylthio, arylthio, heteroarylthio, aralkylthio, heteroaralkylthio, cycloalkyl, cycloalkenyl, heterocyclyl, heterocyclenyl, R60R65N-, R60R65N-alkyl-, R60R65NC(O)- and R60R65NSO2-, wherein R60 and R65 are each independently selected from the group consisting of: hydrogen, alkyl, aryl, and aralkyl; "Ring system 30 substituent" also means a cyclic ring of 3 to 7 ring atoms, wherein 1-2 ring atoms can be heteroatoms, attached to an aryl, heteroaryl, heterocyclyl or heterocyclenyl ring by simultaneously substituting two ring hydrogen atoms on said aryl, heteroaryl, heterocyclyl or heterocyclenyl ring; Non-limiting examples include: RECIEVED IPONZ 22 AUGUST 2011 -48- 2 O y and the like Lines drawn into a ring mean that the indicated bond may be attached to any of the substitutable ring carbon atoms. examples, structural formulae, and any Tables herein is assumed to have the hydrogen atom or atoms to satisfy the valences. One or more compounds of the invention may also exist as, or optionally converted to, a solvate. Preparation of solvates is generally known. Thus, for 10 example, M. Caira et al, J. Pharmaceutical Sci., 93(3), 601-611 (2004) describe the preparation of the solvates of the antifungal fluconazole in ethyl acetate as well as from water. Similar preparations of solvates, hemisolvate, hydrates and the like are described by E. C. van Tonder et al, AAPS PharmSciTech., 5(1). article 12 (2004); and A. L. Bingham et al, Chem. Commun., 603-604 (2001). Atypical, non-limiting, 15 process involves dissolving the inventive compound in desired amounts of the desired solvent (organic or water or mixtures thereof) at a higher than ambient temperature, and cooling the solution at a rate sufficient to form crystals which are then isolated by standard methods. Analytical techniques such as, for example I. R. spectroscopy, show the presence of the solvent (or water) in the crystals as a solvate (or hydrate). 20 The term "pharmaceutical composition" is also intended to encompass both the bulk composition and individual dosage units comprised of more than one (e.g., two) pharmaceutically active agents such as, for example, a compound of the present invention and an additional agent selected from the lists of the additional agents described herein, along with any pharmaceutically inactive excipients. The bulk 25 composition and each individual dosage unit can contain fixed amounts of the aforesaid "more than one pharmaceutically active agents". The bulk composition is material that has not yet been formed into individual dosage units. An illustrative dosage unit is an oral dosage unit such as tablets, capsules, pills and the like. Similarly, the herein-described methods of treating a patient by administering a 30 pharmaceutical composition of the present invention is also intended to encompass the administration of the afore-said bulk composition and individual dosage units. The 5 Any carbon or heteroatom with unsatisfied valences in the text, schemes, RECIEVED IPONZ 22 AUGUST 2011 -49- uses of the invention similarly contemplate the use of the bulk composition and individual dosage units. Prodrugs of the compounds of the invention are also contemplated herein. The term "prodrug", as employed herein, denotes a compound that is a drug 5 precursor which, upon administration to a subject, undergoes chemical conversion by metabolic or chemical processes to yield a compound of formula 1.0 or a salt and/or solvate thereof. A discussion of prodrugs is provided in T. Higuchi and V. Stella, Prodrugs as Novel Delivery Systems (1987) 14 of the A.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design, (1987) Edward B. Roche, ed., American 10 Pharmaceutical Association and Pergamon Press, both of which are incorporated herein by reference thereto. For example, if a compound of formula 1.0, or a pharmaceutically acceptable salt, hydrate or solvate of the compound, contains a carboxylic acid functional group, a prodrug can comprise an ester formed by the replacement of the hydrogen atom of 15 the acid group with a group such as, for example, (Ci-C8)alkyl, (C2-Ci2)alkanoyloxy-methyl, 1-(alkanoyloxy)ethyl having from 4 to 9 carbon atoms, 1-methyl-1-(alkanoyloxy)-ethyl having from 5 to 10 carbon atoms, alkoxycarbonyloxymethyl having from 3 to 6 carbon atoms, 1-(alkoxycarbonyloxy)ethyl having from 4 to 7 carbon atoms, 1-methyl-1-(alkoxycarbonyloxy)ethyl having from 5 to 8 carbon atoms, 20 N-(alkoxycarbonyl)aminomethyl having from 3 to 9 carbon atoms, 1-(N-(alkoxy-carbonyl)amino)ethyl having from 4 to 10 carbon atoms, 3-phthalidyl, 4-crotonolactonyl, gamma-butyrolacton-4-yl, di-N,N-(CrC2)alkylamino(C2-C3)alkyl (such as (3-dimethylaminoethyl), carbamoyl-(Ci-C2)alkyl, N,N-di (CrC2)alkylcarbamoyl-(C1-C2)alkyl and piperidino-, pyrrolidino- or morpholino(C2-C3)alkyl, and the like. 25 Similarly, if a compound of formula 1.0 contains an alcohol functional group, a prodrug can be formed by the replacement of the hydrogen atom of the alcohol group with a group such as, for example, (CrC6)alkanoyloxymethyl, 1-((CrC6)alkanoyl-oxy)ethyl, 1-methyl-1-((CrC6)alkanoyloxy)ethyl, (CrC6)alkoxycarbonyloxymethyl, N-(CrC6)alkoxycarbonylaminomethyl, succinoyl, (CrC6)alkanoyl, a-amino(Cr 30 C4)alkanyl, arylacyl and a-aminoacyl, or a-aminoacyl-a-aminoacyl, where each a- aminoacyl group is independently selected from the naturally occurring L-amino acids, P(0)(0H)2, -P(0)(0(Ci-C6)alkyl)2 or glycosyl (the radical resulting from the removal of a hydroxyl group of the hemiacetal form of a carbohydrate), and the like. RECIEVED IPONZ 22 AUGUST 2011 -50- If a compound of formula 1.0 incorporates an amine functional group, a prodrug can be formed by the replacement of a hydrogen atom in the amine group with a group such as, for example, R70-carbonyl, R70O-carbonyl, NR70R75-carbonyl where R70 and R75 are each independently (CrC10)alkyl, (C3-C7) cycloalkyl, benzyl, or 5 R70-carbonyl is a natural a-aminoacyl or natural a-aminoacyl, —C(0H)C(0)0Y8° wherein Y80 is H, (CrC6)alkyl or benzyl, —C(OY82)Y84 wherein Y82 is (CrC4) alkyl and Y84 is (C-|-C6)alkyl, carboxy (CrC6)alkyl, amino(CrC4)alkyl or mono-N—or di-N,N-(Cr C6)alkylaminoalkyl, —C(Y86)Y88 wherein Y86 is H or methyl and Y88 is mono-N— or di-N,N-(Ci-C6)alkylamino morpholino, piperidin-1-yl or pyrrolidin-1-yl, and the like. 10 This invention also includes the compounds of this invention in isolated and purified form. Polymorphic forms of the compounds of formula 1.0, and of the salts, solvates and prodrugs of the compounds of formula 1.0, are intended to be included in the present invention. 15 Certain compounds of the invention may exist in different isomeric (e.g., enantiomers, diastereoisomers, atropisomers) forms. The invention contemplates all such isomers both in pure form and in admixture, including racemic mixtures. Enol forms are also included. All stereoisomers (for example, geometric isomers, optical isomers and the 20 like) of the present compounds (including those of the salts, solvates and prodrugs of the compounds as well as the salts and solvates of the prodrugs), such as those which may exist due to asymmetric carbons on various substituents, including enantiomeric forms (which may exist even in the absence of asymmetric carbons), rotameric forms, atropisomers, and diastereomeric forms, are contemplated within the 25 scope of this invention. Individual stereoisomers of the compounds of the invention may, for example, be substantially free of other isomers, or may be admixed, for example, as racemates or with all other, or other selected, stereoisomers. The chiral centers of the present invention can have the S or R configuration as defined by the IUPAC 1974 Recommendations. The use of the terms "salt", "solvate" "prodrug" and 30 the like, is intended to equally apply to the salt, solvate and prodrug of enantiomers, stereoisomers, rotamers, tautomers, racemates or prodrugs of the inventive compounds. Diasteromeric mixtures can be separated into their individual diastereomers on the basis of their physical chemical differences by methods well known to those RECIEVED IPONZ 22 AUGUST 2011 -51 - skilled in the art, such as, for example, by chromatography and/or fractional crystallization. Enantiomers can be separated by converting the enantiomeric mixture into a diasteromeric mixture by reaction with an appropriate optically active compound (e.g., chiral auxiliary such as a chiral alcohol or Mosher's acid chloride), separating 5 the diastereomers and converting (e.g., hydrolyzing) the individual diastereomers to the corresponding pure enantiomers. Also, some of the compounds of Formula (I) may be atropisomers (e.g., substituted biaryls) and are considered as part of this invention. Enantiomers can also be separated by use of chiral HPLC column. The compounds of formula 1.0 form salts that are also within the scope of this 10 invention. Reference to a compound of formula 1.0 herein is understood to include reference to salts thereof, unless otherwise indicated. The term "salt(s)", as employed herein, denotes acidic salts formed with inorganic and/or organic acids, as well as basic salts formed with inorganic and/or organic bases. In addition, when a compound of formula 1.0 contains both a basic moiety, such as, but not limited to a 15 pyridine or imidazole, and an acidic moiety, such as, but not limited to a carboxylic acid, zwitterions ("inner salts") may be formed and are included within the term "salt(s)" as used herein. Pharmaceutically acceptable (i.e., non-toxic, physiologically acceptable salts) are preferred. Salts of the compounds of the formula 1.0 may be formed, for example, by reacting a compound of formula 1.0 with an amount of acid or 20 base, such as an equivalent amount, in a medium such as one in which the salt precipitates or in an aqueous medium followed by lyophilization. Acids (and bases) which are generally considered suitable for the formation of pharmaceutically useful salts from basic (or acidic) pharmaceutical compounds are discussed, for example, by S. Berge et al, Journal of Pharmaceutical Sciences (1977) 66(1) 1-19; P. Gould, 25 International J. of Pharmaceutics (1986) 33 201 -217; Anderson et al, The Practice of Medicinal Chemistry (1996), Academic Press, New York; in The Orange Book (Food & Drug Administration, Washington, D.C. on their website); and P. Heinrich Stahl, Camille G. Wermuth (Eds.), Handbook of Pharmaceutical Salts: Properties, Selection, and Use, (2002) Int'l. Union of Pure and Applied Chemistry, pp. 330-331. These 30 disclosures are incorporated herein by reference thereto. Exemplary acid addition salts include acetates, adipates, alginates, ascorbates, aspartates, benzoates, benzenesulfonates, bisulfates, borates, butyrates, citrates, camphorates, camphorsulfonates, cyclopentanepropionates, digluconates, dodecylsulfates, ethanesulfonates, fumarates, glucoheptanoates, glycerophosphates, RECIEVED IPONZ 22 AUGUST 2011 -52- 10 15 20 25 hemisulfates, heptanoates, hexanoates, hydrochlorides, hydrobromides, hydroiodides, 2-hydroxyethanesulfonates, lactates, maleates, methanesulfonates, methyl sulfates, 2-naphthalenesulfonates, nicotinates, nitrates, oxalates, pamoates, pectinates, persulfates, 3-phenylpropionates, phosphates, picrates, pivalates, propionates, salicylates, succinates, sulfates, sulfonates (such as those mentioned herein), tartarates, thiocyanates, toluenesulfonates (also known as tosylates,) undecanoates, and the like. Exemplary basic salts include ammonium salts, alkali metal salts such as sodium, lithium, and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, aluminum salts, zinc salts, salts with organic bases (for example, organic amines) such as benzathines, diethylamine, dicyclohexylamines, hydrabamines (formed with N,N-bis(dehydroabietyl)ethylenediamine), N-methyl-D-glucamines, N-methyl-D-glucamides, t-butyl amines, piperazine, phenylcyclohexyl-amine, choline, tromethamine, and salts with amino acids such as arginine, lysine and the like. Basic nitrogen-containing groups may be quarternized with agents such as lower alkyl halides (e.g. methyl, ethyl, propyl, and butyl chlorides, bromides and iodides), dialkyl sulfates (e.g. dimethyl, diethyl, dibutyl, and diamyl sulfates), long chain halides (e.g. decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides), aralkyl halides (e.g. benzyl and phenethyl bromides), and others. All such acid and base salts are intended to be pharmaceutically acceptable salts within the scope of the invention and all acid and base salts are considered equivalent to the free forms of the corresponding compounds for purposes of the invention. Compounds of formula 1.0, and salts, solvates and prodrugs thereof, may exist in their tautomeric form (for example, as an amide or imino ether). All such tautomeric forms are contemplated herein as part of the present invention. In hetero-atom containing ring systems of this invention, there are no hydroxyl groups on carbon atoms adjacent to a N, O or S, and there are no N or S groups on carbon adjacent to another heteroatom. Thus, for example, in the ring: n h there is no -OH attached directly to carbons marked 2 and 5. RECIEVED IPONZ 22 AUGUST 2011 -53- The compounds of formula 1.0 may exist in different tautomeric forms, and all such forms are embraced within the scope of the invention. Also, for example, all keto-enol and imine-enamine forms of the compounds are included in the invention. Tautomeric forms such as, for example, the moieties: are considered equivalent in certain embodiments of this invention. The term "substituted" means that one or more hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the designated atom's normal valency under the existing circumstances is not exceeded, 10 and that the substitution results in a stable compound. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds. By "stable compound" or "stable structure" is meant a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent. 15 The term "optionally substituted" means optional substitution with the specified groups, radicals or moieties. The term "purified", "in purified form" or "in isolated and purified form" for a compound refers to the physical state of said compound after being isolated from a synthetic process or natural source or combination thereof. Thus, the term "purified", 20 "in purified form" or "in isolated and purified form" for a compound refers to the physical state of said compound after being obtained from a purification process or processes described herein or well known to the skilled artisan, in sufficient purity to be characterizable by standard analytical techniques described herein or well known to the skilled artisan. 25 When a functional group in a compound is termed "protected", this means that the group is in modified form to preclude undesired side reactions at the protected site when the compound is subjected to a reaction. Suitable protecting groups will be recognized by those with ordinary skill in the art as well as by reference to standard textbooks such as, for example, T. W. Greene et al, Protective Groups in organic 30 Synthesis (1991), Wiley, New York. and 5 h RECIEVED IPONZ 22 AUGUST 2011 -54- When any variable (e.g., aryl, heterocycle, R3, etc.) occurs more than one time in any moiety or in any compound of formula 1.0, its definition on each occurrence is independent of its definition at every other occurrence. As used herein, the term "composition" is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts. The present invention also embraces isotopically-labelled compounds of the present invention which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, such as 2H, Certain isotopically-labelled compounds of formula 1.0 (e.g., those labeled with 3H and 14C) are useful in compound and/or substrate tissue distribution assays. Tritiated (i.e., 3H) and carbon-14 (i.e., 14C) isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium (i.e., 2H) may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and hence may be preferred in some circumstances. Isotopically labelled compounds of formula 1.0 can generally be prepared by following procedures analogous to those disclosed in the Schemes and/or in the Examples hereinbelow, by substituting an appropriate isotopically labelled reagent for a non-isotopically labelled reagent. This invention provides compounds of formula 1.0: 3 H, 13C, 14C, 15N, 180, 170, 31P, 32P, 35S, 18F, and 36CI, respectively. hn * ■s q (1.0) or the pharmaceutically acceptable salts thereof, wherein: RECIEVED IPONZ 22 AUGUST 2011 -55- Y1, Y2, and Y3 are each independently selected from the group consisting of: -CH=, -N= and -CR9= (preferably Y1, Y2, and Y3 are each -CH=); z is 1 to 3 (i.e., 1, 2 or 3, and preferably 1); Q is a substituent selected from the group consisting of; r3 R" r6 r5 (2.4) r4 r4 r4 (2.5) r4 R4 (2.6) (2.13) Rl .R7 l^-r6 r3- c R , r3 r4 R R' (2.16) 15 RECIEVED IPONZ 22 AUGUST 2011 5 Each Q1 represents a ring independently selected from the group consisting of: cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl, wherein said substituted rings are substituted with 1 to 3 substituents independently selected from the group 1 n 1 10 consisting of: the R moieties; provided that when Q is aryl, heteroaryl, substituted aryl or substituted heteroaryl then the carbon atoms at the ring junction (i.e., the two carbon atoms common to the fused rings) are not substituted; Q2 represents a ring selected from the group consisting of: cycloalkyl, substituted cycloalkyl, heterocycloalkyl, and substituted heterocycloalkyl, wherein said 15 substituted rings are substituted with 1 to 3 substituents independently selected from the group consisting of: the R10 moieties; Z1 represents -(C(R24)2)W- wherein each R24 is independently selected from the group consisting of: H, alkyl (e.g., Ci to C6 alkyl, for example methyl) and F, and wherein w is 1, 2 or 3, and generally w is 1 or 2, and usually w is 1, and wherein in 20 one example each R24 is H, and in another example w is 1, and in another example each R24 is H and w is 1, preferably w is 1 and each R24 is H (i.e., preferably Z1 is -CH2-); Z2 is selected from the group consisting of: -N(R44)-, -O- and -C(R46)2- (e.g., Z2 is-NH-, -O- or-CH2-); 25 m is 1 to 6; RECIEVED IPONZ 22 AUGUST 2011 -57 - n is 1 to 6; p is 0 to 6; t is 0, 1, or 2; R1 is selected from the group consisting of: 5 (1) -CN, (2) -N02, (3) -OR10, (4) -SR10, (5) -N(R10)2, 10 (6) R10, (7) -C(0)R1° (in one example R10 is a 4 to 6 membered heterocycloalkyl ring, in another example R10 is a 4 to 6 membered heterocycloalkyl ring comprising one nitrogen atom, and in another example R10 is a 4 to 6 membered heterocycloalkyl ring comprising one nitrogen atom wherein said ring is bound to the carbonyl moiety (- 15 C(O)-) through the ring nitrogen), (8) -(C(R30)2)n-NR32-C(O)-R10 (e.g., -(CH2)n-NH-C(0)-R1°, for example wherein n is 1), wherein in one example n is 1, each R30 is H, R32 is H, and R10 is selected from the group consisting of: cycloalkyl (e.g., cyclopropyl) and alkyl (e.g., methyl and i-propyl), and wherein in another example n is 1, each R30 is H, R32 is H, 20 and R10 is selected from the group consisting of: methyl, i-propyl and cyclopropyl, (9) -(C(R30)2)n-NR32-S(O)t-R10 (e.g., -(CH2)n-NH-S(0)t-R10, for example wherein n is 1 and t is 2) wherein in one example n is 1, each R30 is H, R32 is H, t is 2, and R10 is selected from the group consisting of: cycloalkyl (e.g., cyclopropyl) and alkyl (e.g., methyl and i-propyl), and wherein in another example n is 1, each R30 is H, 25 R32 is H, t is 2, R10 is selected from the group consisting of: methyl, i-propyl and cyclopropyl, and wherein in another example n is 1, each R30 is H, R32 is H, t is 2, and R10 is methyl, (10) -(C(R )2)n-NR -C(0)-N(R )-R (e.g., -(CH2)n-NH-C(0)-NH-R'u, for example wherein n is 1) wherein in one example n is 1, each R30 is H, each R32 is H, 30 and R10 is alkyl (e.g., methyl and i-propyl), and wherein in another example n is 1, each R30 is and i-propy each R30 is H, each R32 is H, and R10 is selected from the group consisting of: methyl (11) RECIEVED IPONZ 22 AUGUST 2011 -58- 10 15 20 O wherein in one example n is 1 and each R30 is H, i.e., a moiety of the formula: (12) -CF3, (13) -C(0)0R1° wherein in one example R10 is selected from the group consisting of: H, alkyl (e.g., methyl and ispropyl) and cyclopropyl (e.g., cyclopropyl), and wherein in another example R10 is selected from the group consisting of: H and alkyl, and wherein in another example R10 is selected from the group consiting of: H and methyl, (14) -(C(R30)2)nR13 (e.g., -(CH2)nR13) wherein in one example n is 1, each R30 is H, and R13 is selected from the group consisting of: -OH and -N(R10)2, wherein each R10 is independently selected, and wherein in another example n is 1, each R30 is H, and R13 is selected from the group consisting of: -OH and -N(R10)2, and each R10 is H (i.e., R13is -OH or-NH2), (15) alkenyl (e.g., -CH=CHCH3), (16) -NR32-C(0)-R14 (e.g., -NH-C(0)-R14) wherein in one example R32 is H and R14 is selected from the group consisting of: cycloalkyl (e.g., cyclopropyl), alkyl (e.g., methyl and propyl), aryl (e.g., phenyl), amino (i.e., -NH2), and heteroaryl (e.g., pyridyl, such as, for example 2- pyridyl, 3-pyridyl, 4-pyridyl, pyrazolyl and imidazolyl), and wherein in another example R32 is H and R14 is selected from the group consisting of: cyclopropyl, methyl, propyl, phenyl, and amino, o (17) R1 o I —n—c—n(r10)2 o wherein each R10 is independently selected, for example: (a) in one example moiety (20) is: RECIEVED IPONZ 22 AUGUST 2011 -59- h —n-c-n(r10)2 o 10 wherein each R is independently selected, (b) in another example moiety (20) is: n—c—n—r10 ii h o , and 5 (c) in another example moiety (20) is: h —n-c—n—r10 ii h O wherein R10 is selected from the group consisting of: aryl (e.g., phenyl) and alkyl (e.g., ethyl, and preferably R10 is phenyl or ethyl, (18) r10 10 n s(0)t r10 wherein each R10 is independently selected, and wherein in one example each R10 is independently selected and t is 2, and wherein in another example moiety (18) is -NH-S(0)t-R1°, and wherein in another example moiety (18) is -NH-S(0)t-R1° wherein t is 2, and wherein in another example moiety (18) is -NH-S(0)t-R1°. t is 2, and R10 is 15 alkyl (e.g., methyl), (19) t nh / c nh s—c—N—R15 ( e.g., ^—c—N—R15 r32 (also written as -C(NH)N(R15)R32 and -C(NH)NH(R15), respectively), wherein in one example R15 is -OH, and in another example R32 is H and R15 is -OH, 20 (20) -C(O)-NR32-(C(R30)2)p-OR10 (e.g., -C(0)-NH-(CH2)p-0R1°, and, for example, -C(0)-NH-(CH2)p-0R10 wherein p is 2) wherein: (a) in one example p is 2, (b) in another example R32 is H, (c) in another example R10 is selected from the group consisting of: H 25 and alkyl (e.g., methyl), (d) in another example R10 is selected from the group consisting of: H and alkyl (e.g., methyl), and R32 is H, RECIEVED IPONZ 22 AUGUST 2011 -60- (e) in another example R10 is selected from the group consisting of: and methyl, H and alkyl (e.g., methyl), R32 is H, an p is 2, (f) in another example R32 is H, each R30 is H, and R10 is alkyl, (g) in another example R32 is H, each R30 is H, and R10 is methyl, (h) in another example R32 is H, each R30 is H, p is 2 and R10 is alkyl, (i) in another example R32 is H, each R30 is H, p is 2 and R10 is 1 n 1 n (21) -C(0)N(R )2 wherein each R is independently selected, and 10 preferably each R10 is independently selected from the group consisting of: (a) H, (b) alkyl (e.g., methyl, butyl, and i-propyl), (c) heteroaryl (e.g., pyridyl), (d) aryl (e.g., phenyl), and (e) cycloalkyl (e.g., cyclopropyl), wherein for example, each R10 is selected from the group consisting of: H, methyl, butyl, i-propyl, pyridyl, phenyl and cyclopropyl, wherein, for example, said -C(O)N(R10)2 moiety is selected from the 15 group consisting of: -C(0)NH2, -C(0)NH(CH3), -C(0)NH(CH)(CH3)2 (i.e., -C(0)NH(i-propyl)), -C(0)NH(C4H9), -C(0)NH(C6H5) (i.e., -C(0)NH(phenyl)), -C(0)NH(C3H5) (i.e., -C(0)NH(cyclopropyl), and -C(0)NH(C5H4N) (i.e., -C(0)NH(pyridyl), such as <—c(0)nh-<\ n 20 (22) -C(0)-NR32-C(R18)3 (e.g., -C(0)-NH-C(R18)3) wherein each R18 is independently selected from the group consisting of: R10 and -C(0)0R19, and R19 is selected from the group consisting of:alkyl (e.g., methyl) and substituted arylalkyl (e.g., -CH2C6H4OH (i.e.,hydroxybenzyl) such as, for example, -p-CH2C6H4OH (i.e., p-OHbenzyl), and wherein: 25 (a) in one example R18 and R19 are as defined above with the proviso 1 Q HQ that at least one R substitutent is other than H (e.g., in one example one R is H 18 1 ft and the remaining two R groups are other than H, and in another example two R substituents are H and the remaining R18 substituent is other than H), (b) in another example R18 is selected from the group consisting of: 30 H, aryl (e.g., phenyl), substituted aryl (e.g., substituted phenyl, such as, for example halophenyl-, such as, for example, flurophenyl (e.g., o-F-phenyl)), and -C(0)0R 19 RECIEVED IPONZ 22 AUGUST 2011 -61 - (c) in another example R18 is selected from the group consisting of: H, phenyl, flurophenyl (e.g., o-F-phenyl), -C(0)0CH3, -C(0)0CH2C6H40H (i.e., -C(0)0(0Hbenzyl), such as, -C(0)0(p-0Hbenzyl)), (d) in another example R18 is selected from the group consisting of: 5 H, aryl (e.g., phenyl), substituted aryl (e.g., substituted phenyl, such as, for example halophenyl-, such as, for example, flurophenyl (e.g., o-F-phenyl)), and -C(0)0R19, provided that at least one R18 substitutent is other than H (e.g., in one example one R18 is H and the remaining two R18 groups are other than H, and in another example two R18 substituents are H and the remaining R18 substituent is other than H), 10 (e) in another example R18 is selected from the group consisting of: H, phenyl, flurophenyl (e.g., o-F-phenyl), -C(0)0CH3, -C(0)0CH2C6H40H (i.e., -C(0)0(0Hbenzyl), such as, -C(0)0(p-0Hbenzyl)), provided that at least one R18 substitutent is other than H (e.g., in one example one R18 is H and the remaining two R18 groups are other than H, and in another example two R18 substituents are H and 15 the remaining R18 substituent is other than H), (f) in another example R32 is H, and each R18 is independently selected from the group consisting of: R10 and -C(0)0R19, and R19 is selected from the group consisting of:alkyl (e.g., methyl) and substituted arylalkyl (e.g., -CH2C6H4OH (i.e.,hydroxybenzyl) such as, for example, -p-CH2C6H4OH (i.e., p- 20 OHbenzyl), (g) in another example R32 is H and R18 and R19 are as defined in paragraph (a), (h) in another example R32 is H and R18 and R19 are as defined in paragraph (b), 25 (i) in another example R32 is H and R18 and R19 are as defined in paragraph (c), (j) in another example R32 is H and R18 and R19 are as defined in paragraph (d), (k) in another example R32 is H and R18 and R19 are as defined in 30 paragraph (e), and (I) in another example R32 is H and R18 and R19 are as defined in paragraph (f), (23) -C(O)-NR32-(C(R30)2)n-C(O)-N(R10)2 (e.g., -C(0)-NH-(CH2)n-C(0)-NH2), and wherein: RECIEVED IPONZ 22 AUGUST 2011 -62- op in one example R is H, on in another example each R is H, in another example n is 1, in another example n is 1 and R32 is H, 5 in another example each R10 is H, in another example R32 is H and each R30 is H, in another example R32 is H, each R30 is H and n is 1, in another example R32 is H, each R30 is H, n is 1, and each R10 is H, op on in another example R is H, n is 1, each R is independently 10 selected from the group consisting of: H and alkyl, and each R10 is independently selected from the group consisting of: H and alkyl, and in another example R32 is H, n is 1, and each R30 is independently selected from the group consisting of: H, methyl, ethyl and i-propyl (or each R30 is independently selected from the group consisting of H and i-propyl, or one R30 is i-15 . propyl and the other R30 is H), and each R10 is independently selected from the group consisting of: H methyl, ethyl and i-propyl (or each R10 is H), (24) heterocycloalkenyl, such as, for example: ,n. n- wherein r is 1 to 3, and wherein in one example r is 1, i.e., in one example the 20 heterocycloalkenyl is dihydroimidazolyl, such as, for example: N (25) (26) arylalkenyl- (aralkenyl-), for example, aryl(C2 to C6)alkenyl-, such as 25 for example, -CH=CH-phenyl; R2 is selected from the group consisting of; (1)H, RECIEVED IPONZ 22 AUGUST 2011 -63- 10 15 20 (2) -CN, (3) halo (e.g., F), (4) alkyl (e.g., Ci to C6 alkyl, such as, for example, methyl, ethyl and propyl), (5) substituted alkyl (e.g., substituted Ci to C6 alkyl, such as, for example, substituted methyl and substituted ethyl) wherein said substituted alkyl is substituted with 1 to 3 substitutents (e.g., 1 substituent) selected from the group consisting of: (a) -OH, (b) -O-alkyl (e.g., -0-(CrC3alkyl), (c) -O-alkyl (e.g., -0-(CrC3alkyl)) substituted with 1 to 3 F atoms (examples of said -O- substituted alkyl portion include, but are not limited to, -OCHF2 and -OCF3), and (d) -N(R40)2 wherein each R40 is independently selected from the group consisting of: (i) H, (ii) Ci-C3 alkyl (e.g., methyl), (iii) -CF3, and (e) halo (for example F, CI, and Br, and also for example F, examples of a halo substituted alky group include, but are not limited to, -CHF2) (examples of said substituted alkyl groups described in (5) include but are not limited to-CH(OH)CH3), (6) alkynyl (e.g., ethynyl), (7) alkenyl (e.g., -CH2-CH=CH2), (8)-(CH2)mR11, (9) -N(R26)2, (10) -OR23 (e.g., -OH, -OCH3 and -O-phenyl), (11) -N(R26)C(0)R42 wherein in one example R26 is H or Ci to C6 alkyl (e.g., methyl) and R42 is alkyl (e.g., methyl), and in another example -N(R26)C(0)R42 is -NHC(0)CH3, (12) cycloalkyl (e.g., C3 to C6 cycloalkyl, such as, for example, cyclopropyl and cyclohexyl), (13) cycloalkylalkyl (e.g., C3 to C6 cycloalkyl-(Ci to C3)alkyl-, such as, for example, cyclopropyl-CH2- and cyclohexyl-CH2-), RECIEVED IPONZ 22 AUGUST 2011 -64- (15) -0-(substituted alkyl) wherein said substituted alkyl is substituted with 1 to 3 F atoms (examples of said -0-(substituted alkyl) moiety include, but are not limited to, -OCHF2 and -OCF3), (16) -S(0)t-alkyl, such as, for example, (a) -S-alkyl (i.e., t is 0) such as, for 5 example, -S-CH3, and (b) -S(0)2-alkyl (i.e., t is 2) such as, for example, -S(0)2CH3, (17) -C(0)-alkyl (e.g.,-C(0)CH3), (18) N—O—H £ H S —q—alkyl wherein methyl is an example of said alkyl moiety, 10 (19) N—O—alkyl ^ —C—alkyl wherein each alkyl is independently selected, examples of this moiety include, but are not limited to: n—o—ch3 £ II ?—c-ch3 j 15 (20) O h ii N—N—C—alkyl § —C—alkyl which each alkyl is independently selected, examples of this moiety include, but are not limited to, o h ii n—n—c—ch3 £ H s_c_GH 20 (21) alkyl I o I II N—N—C—alkyl II -C—alkyl RECIEVED IPONZ 22 AUGUST 2011 -65- whereiri each alkyl is independently selected, (22) -N(R48)-C(0)-R48 wherein each R48 is independently selected from the group consisting of: H and alkyl (e.g., Ci to C6 alkyl, such as, for example, methyl), and wherein examples of this moiety include, but are not limited to, -NH-C(0)-H, and -N(CH3)-C(0)H, and (23) -C(0)-alkyl, such as, for example, -C(0)-(CrC6 alkyl), such as, for example, -C(0)CH3; and wherein: (a) in one example said (14) moiety is (c) in another example Z2 is -NH- in (a), (d) in another example Z2 is -NH- in (b), (e) in another example Z2 is -O- in (a), (f) in another example Z2 is -O- in (b), (g) in another example Z2 is -CH2- in (a), (h) in another example Z2 is -CH2- in (b), (i) in another example R2 is -(CH2)mR11 and m is 1, (j) in another example R2 is -N(R26)2, (k) in another example R2 is -N(R26)2, and each R26 is H (i.e., R2 is -NH2), (I) in another example R2 is -OR23, and (m) in another example R2 is -OH (i.e., R23 is H); each R3, R4, R5, R6 and R7 is independently selected from the group consisting of: (1) H, (2) alkenyl (e.g., -CH2CH=CH2), (3) substituted alkenyl, (4) alkyl, (5) substituted alkyl, and n is 1, (b) in another example said (14) moiety is —ch2-n z2 \—/ (i.e., n is 1, and each R30 is H), RECIEVED IPONZ 22 AUGUST 2011 -66- (6) cycloalkyl, (7) substituted cycloalkyl, (8) cycloalkylalkyl-, (9) substituted cycloalkylalkyl-, 5 (10) heterocycloalkyl, (11) substituted heterocycloalkyl, (12) heterocycloalkylalkyl-, (13) substituted heterocycloalkylalkyl-, (14) -C(0)R1° wherein in one example R10 is selected from the group 10 consisting of: alkyl (e.g., Ci to C6, e.g., methyl), (15) arylheteroaryl- (e.g., phenylthiadiazolyl-), (16) substituted arylheteroaryl- (e.g., substituted phenylthiadiazolyl-), (17) heteroarylaryl-, such as, for example, pyrimidinylphenyl-, pyrazinylphenyl-, pyridinylphenyl- (i.e., pyridylphenyl-), furanylphenyl-, thienylphenyl-, 15 and thiazolylphenyl-, (18) substituted heteroarylaryl-, such as, for example, substituted pyrimidinylphenyl-, substituted pyrazinylphenyl-, substituted pyridinylphenyl- (i.e., substituted pyridylphenyl-), substituted furanylphenyl-, substituted thienylphenyl-, substituted thiazolylphenyl-, and substituted pyrimidinylphenyl, 20 (19) aryl (e.g., phenyl), (20) substituted aryl (e.g., substituted phenyl), (21) heteroaryl (e.g., thiazolyl, thienyl, pyridyl, and pyrimidinyl), (22) substituted heteroaryl (e.g., substituted thiazolyl, substituted pyridyl and substituted pyrimidinyl), examples of substituted heteroaryl groups include, for 25 example bromothiazolyl-, bromopyrimidinyl-, fluoropyrimidinyl-, and ethenylpyrimidinyl' (23) heteroarylheteroaryl- (e.g., pyrimidinylpyridyl-, and pyrimidinylthiazolyl-), (24) substituted heteroarylheteroaryl- (e.g., substituted pyrimidinyl- pyridyl- 30 ), (25) arylaminoheteroaryl- (e.g., phenyl-NH-oxadiazolyl-), (26) substituted arylaminoheteroaryl- (e.g., substituted phenyl-NH-oxadiazolyl-), RECIEVED IPONZ 22 AUGUST 2011 -67- (27) arylalkynyl- (e.g., aryl(C2 to C4)alkynyl such as, for example phenylethynyl-), (28) substituted arylalkynyl- (e.g., substituted aryl(C2 to C4)alkynyl-, such as, for example, substituted phenylethynyl-), 5 (29) heteroarylalkynyl- (e.g., heteroaryl(C2 to C4)alkynyl-, such as, for example, pyrimidinylethynyl-), (30) substituted heteroarylalkynyl- (e.g., substituted heteroaryl(C2 to C4)alkynyl-, such as, for example substituted pyrimidinylethynyl-), wherein said R3, R4, R5, R6 and R7 substituted groups (7), (9), (11), (13), (16), 10 (18), (20), (22), (24), (26), (28) and (30) are substituted with 1 to 3 substituents independently selected from the group consisting of: -NH2, alkyl (e.g., Ci to C6 alkyl, e.g., methyl, ethyl, and i-propyl), alkenyl (e.g., C2 to C6 alkenyl, such as, for example -CH=CH2), halo (e.g., F, CI and Br, and in another example F), -C(0)-NH-R28 (e.g., -C(0)-NH-CH3), -C(0)0R28 (e.g., -C(0)0C2H5), and -C(0)R28 ( e.g., -C(0)CH3), 15 wherein said R3,.R4, R5, R6 and R7 substituted groups (3) and (5) are substituted with 1 to 3 substituents independently selected from the group consisting of: -NH2, halo (e.g., F, CI and Br, and in another example F), -C(0)-NH-R28 (e.g., -C(0)-NH-CH3), -C(0)0R28 (e.g., -C(0)0C2H5), and -C(0)R28 (e.g., -C(0)CH3), and wherein: 20 in one example said substituted heteroarylaryl (moiety (18) above) is substituted with 1 to 3 substituents independently selected from the group consisting of: -NH2, alkyl (e.g., Ci to C6 alkyl, e.g., methyl), halo (e.g., F, CI and Br, such as, for example F), in another example said substituted aryl (moiety (20) above) is substituted 25 with 1 to 3 substituents independently selected from the group consisting of halo (e.g., F, CI and Br), -C(0)-NH-R28 (e.g., -C(0)-NH-CH3), -C(0)0R28 (e.g., -C(0)0-C2H5), and -C(0)R28 (e.g., -C(0)CH3), and in another example said substituted heteroaryl (moiety (22) above) is substituted with 1 to 3 substitutents selected from the group consisting of: halo (e.g., 30 Br, F, and CI), alkenyl (e.g., C2 to C6 alkenyl, such as, for example, -CH=CH2); R5A is selected from the group consisting of: halo (for example, F, CI, and Br, and in another example F), -OH, and -O-alkyl (such as, for example, -0-(Ci to C6 alkyl), also, for example, -0-(Ci to C3 alkyl), also for example, -0-(C-i to C2 alkyl), and in one example -0-CH3); RECIEVED IPONZ 22 AUGUST 2011 -68- R8 is selected from the group consisting of: H, -OH, -N(R10)2 (e.g., -NH2), -NR10C(O)R12 (e.g., -NHC(0)CH3), and alkyl (e.g., methyl); each R9 is independently selected from the group consisting of:halogen, -CN, -N02, -OR10, -SR10, -N(R10)2, and R10; 5 each R10 is independently selected from the group consisting of: H, alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, alkylheteroaryl-, alkylaryl-, substituted alkyl, substituted aryl, substituted arylalkyl, substituted heteroaryl, substituted heteroarylalkyl, substituted cycloalkyl, substituted cycloalkylalkyl, substituted heterocycloalkyl, substituted 10 heterocycloalkylalkyl, substituted alkylheteroaryl-, substituted alkylaryl-, heterocycloalkenyl and substituted heterocycloalkenyl, and wherein: said R10 substituted alkyl is substituted with 1 to 3 substituents independently 15 selected from the group consisting of: -NH2, -NHR20, -N02, -CN, -OR26, halo (e.g., F, CI and Br, and in another example F), -C(0)-NH-R26 (e.g., -C(0)-NH-CH3, i.e., R26 is alkyl, such as methyl), -C(0)0R26 (e.g., -C(0)0C2H5, i.e., R26 is alkyl, such as ethyl), and -C(0)R26 (e.g., -C(0)CH3, i.e., R26 is alkyl, such as methyl), and 20 substituted heteroarylalkyl, substituted cycloalkyl, substituted cycloalkylalkyl, substituted heterocycloalkyl, substituted heterocycloalkylalkyl, substituted alkylheteroaryl- and substituted alkylaryl- are substituted with 1 to 3 substituents independently selected from the group consisting of: (1) -NH2, (2) -N02, (3) -CN, (4) -OH, (5) -OR20, (6) -OCF3, (7) alkyl (e.g., Ci to C6 alkyl) substituted with 1 to 3 25 independently selected halo atoms (e.g., F, CI and Br), examples of the substituted alkyl include, but are not limited to, -CF3, -CHF2 and-CH2F, (8) -C(0)R38 (e.g., R38 is H or alkyl (e.g., Ci to C6 alkyl, such as, for example, methyl or ethyl), for example, R38 is alkyl (e.g., methyl), thus, an example of -C(0)R38 is -C(0)CH3), (9) alkyl (e.g., Ci to C6 alkyl, e.g., methyl, ethyl, and i-propyl), (10) alkenyl (e.g., C2 to C6 alkenyl, such as, 30 for example -CH=CH2), (11) halo (e.g., F, CI and Br, and in another example F), (12) -C(0)-NH-R26 (e.g., -C(0)-NH-CH3), (13) -C(0)0R38 (e.g., R38 is H or alkyl (e.g., Ci to C6 alkyl, such as, for example, methyl or ethyl), for example, R38 is alkyl (e.g., 1 n said R substituted aryl, substituted arylalkyl, substituted heteroaryl RECIEVED IPONZ 22 AUGUST 2011 -69- methyl or ethyl), thus, for example, -C(0)0R38 is -C(0)0C2H5), (14) -C(O)-NR32-(C(R30)2)n-N(R38)2 (e.g., -C(0)-NH-(CH2)n-N(R38)2) (wherein (a) in one op on example R is H, (b) in another example each R is H, (c) in another example n is 2, (d) in another example each R38 is independently selected, (e) in another example 5 each R38 is independently selected from the group consisting of: H and alkyl (e.g., methyl), (f) in another example R32 is H, each R30 is H, and each R38 is independently selected, (g) in another example R32 is H, each R30 is H, and each R38 is independently selected from the group consisting of: H and alkyl (e.g., methyl), (15) -S(0)tR38 (wherein in one example t is 2, and in another example R38 is alkyl 10 (e.g., methyl), and in another example t is 2 and R38 is alkyl (e.g., methyl)), (16) -C(0)-NR32-R38 (e.g., -C(0)-NR32-R38) (wherein one example R32 is H, in another example R38 is alkyl (e.g., propyl), and in another example R32 is H and R38 is alkyl (e.g., propyl)), (17) -NR32-C(0)-R38 (e.g., -NH-C(0)-R38) (wherein in one example R32 is H, in another example R38 is alkyl (e.g., methyl), and in another example R32 is H 15 and R38 is alkyl (e.g., methyl)), c n r32 / c n \ (18) |—Ji_N_R38 (e.g., ?—c—NH—R33j Op OQ (wherein in one example R is H, in another example R is H, and in another example R32 is H and R38 is H), (19) -NHR20 (e.g., -NHCH3, -NHC2H5), and (20) cycloalkyl (e.g., C3 to C6 cycloalkyl, such as, for example, cyclopropyl); 20 R11 is selected from the group consisting of: F, -OH, -CN, -OR10, -NHNR1R10, -SR10 and heteroaryl (e.g., triazolyl, such as, for example, A-v) NvN J. j R12 is selected from the group consisting of: alkyl, aryl, heteroaryl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl and heterocycloalkylalkyl; 25 R14 is selected from the group consisting of: alkyl, aryl, heteroaryl, cycloalkyl, cycloalkylalkyl-, heterocycloalkyl, alkylheterocycloalkyl, heterocycloalkylalkyl-, alkylheteroaryl- and alkylaryl-; R15 is selected from the group consisting of: H, -OH, alkyl, aryl, heteroaryl, cycloalkyl, cycloalkylalkyl-, heterocycloalkyl and heterocycloalkylalkyl-, alkylheteroaryl-30 and alkylaryl-; RECIEVED IPONZ 22 AUGUST 2011 -70- R20 represents alkyl (e.g., C-i to C6 alkyl, such as, for example, methyl or ethyl); R23 is selected from the group consisting of: H, alkyl (e.g., Ci to C6 alkyl, such as, for example, methyl and i-propyl), aryl (e.g., phenyl), cycloalkyl (e.g., C3 to C6 cycloalkyl, such as, for example, cyclopropyl and cyclohexyl), and cycloalkylalkyl-5 (e.g., C3 to C6 cycloalkylalkyl-, such as -(CH2)n-cycloalkyl, such as -(CH2)n-(C3 to C6)cycloalkyl, wherein each H of each -(CH2)n- moiety can independently be substituted with an alkyl group (e.g., Ci to C6 alkyl, such as, for example, methyl), and wherein in one example n is 1 and the -CH2- moiety is not substituted, that is, -CH2-cycloalkyl, such as, -CH2-cyclopropyl, is an example of said cycloalkylalkyl- moiety); 10 each R26 is independently selected from the group consisting of: H and alkyl (e.g., Ci to C6 alkyl, such as, for example, methyl and ethyl); R28 is alkyl (e.g., C-i to C6 alkyl, such as, for example, methyl or ethyl); each R30 is independently selected from the group consisting of: H, alkyl (e.g., Ci to C6 alkyl, such as, for example methyl, ethyl and i-propyl), and F, and wherein in 15 one example each R30 is H; each R32 is independently selected from the group consisting of: H and alkyl (e.g., Ci to C6 alkyl, such as, for example methyl, ethyl and propyl), and wherein each R32 is generally H; each R35 is independently selected from the group consisting of: H and Ci to 20 C6 alkyl (e.g., methyl, ethyl, i-propyl, and propyl), and wherein in one example both R35 substitutents are the same or different alkyl groups (e.g., both R35 groups are the same alkyl group, such as methyl), and in another example one R35 group is H and the other R35 group is alkyl, such as methyl), and in another example each R35 is preferably H; 25 R36 is selected from the group consisting of: H, alkyl (e.g., Ci to C6 alkyl, such as, for example, methyl, ethyl and propyl), and -O-alkyl (e.g., -0-(Ci to Ce) alkyl, such as, for example, -0-(Ci to C2) alkyl, such as, for example, -OCH3), and preferably R36 is selected from the group consisting of H and methyl, and more preferably R36 is H; each R38 is independently selected from the group consisting of: H, alkyl, aryl, 30 arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, alkylheteroaryl-, alkylaryl-, substituted alkyl, substituted aryl, substituted arylalkyl, substituted heteroaryl, substituted heteroarylalkyl, substituted cycloalkyl, substituted cycloalkylalkyl, substituted heterocycloalkyl, substituted RECIEVED IPONZ 22 AUGUST 2011 -71 - 10 15 20 25 heterocycloalkylalkyl, substituted alkylheteroaryl- and substituted alkylaryl-, and wherein: said R38 substituted alkyl is substituted with 1 to 3 substituents independently selected from the group consisting of: -NH2, -N02, -CN, -OR26, halo (e.g., F, CI and Br, and in another example F), -C(0)-NH-R28 (e.g., -C(0)-NH-CH3), -C(0)0R28 (e.g., -C(0)0C2H5), and -C(0)R28 ( e.g., -C(0)CH3), and said R38 substituted aryl, substituted arylalkyl, substituted heteroaryl, substituted heteroarylalkyl, substituted cycloalkyl, substituted cycloalkylalkyl, substituted heterocycloalkyl, substituted heterocycloalkylalkyl, substituted alkylheteroaryl- and substituted alkylaryl- are substituted with 1 to 3 substituents independently selected from the group consisting of: (1) -NH2, (2) -N02, (3) -CN, (4) -OH, (5) -OR20, (6) -OCF3, (7) -CF3, (8) -C(0)R26 (e.g., R26 is H or C1 to C6 alkyl, such as, for example, methyl or ethyl, for example, R26 is alkyl (e.g., methyl), thus, an example of-C(0)R26 is -C(0)CH3), (9) alkyl (e.g., Ci to C6 alkyl, e.g., methyl, ethyl, and i-propyl), (10) alkenyl (e.g., C2 to C6 alkenyl, such as, for example -CH=CH2), (11) halo (e.g., F, CI and Br, and in another example F), (12) -C(0)-NH-R26 (e.g., -C(0)-NH-CH3), (13) -C(0)0R26 (e.g., R26 is H or e.g., Ci to C6 alkyl, such as, for example, methyl or ethyl, for example, R26 is alkyl (e.g., methyl or ethyl), thus, for example, -C(0)0R26 is -C(0)0C2H5), (14) -C(O)-NR32-(C(R30)2)n-N(R26)2 (e.g., -C(0)-NH-(CH2)n-N(R26)2) (wherein (a) in one example R32 is H, (b) in another example each R30 is H, (c) in another example n is 2, (d) in another example each R26 is independently selected, (e) in another example each R26 is independently selected from the group consisting of: H and methyl), (f) in another example R32 is H, each R30 is H, and each R26 is independently selected, (g) in another example R32 is H, each R30 is H, and each R26 is independently selected from the group consisting of: H and methyl), (15) -S(0)tR26 (wherein in one example t is 2, and in another example R26 is methyl, and in another example t is 2 and R26 is methyl), (16) -C(0)N(R32)(R26) (wherein in one example R32 is H, in another example R26 is alkyl (e.g., propyl), and in another example R32 is H and R26 is alkyl (e.g., propyl)), (17) -NR32C(0)R26 (e.g., -NHC(0)R26) (wherein in one example R32 is H, in another example R26 is alkyl (e.g., methyl), and in another example R32 is H and R26 is alkyl (e.g., methyl)), RECIEVED IPONZ 22 AUGUST 2011 -72- op pC (wherein in one example R is H, in another example R is H, and in another example R32 is H and R26 is H); and (19)-NHR20; R42 is selected from the group consisting of: alkyl (e.g., Ci to C6 alkyl, such as, for example -CH3), aryl (e.g., phenyl), heteroaryl (e.g., thiazolyl and pyridyl), and cycloalkyl (e.g., C3 to C6 cycloalkyl, such as, for example, cyclopropyl); R44 is selected from the group consisting of: H, alkyl (e.g., Ci to C6 alkyl, such as, for example, Ci to C3 alkyl, such as, for example, methyl, ethyl and i-propyl), cycloalkyl (e.g., C3 to C6 cycloalkyl, such as, for example, cyclopropyl and cyclohexyl), and cycloalkylalkyl (e.g., (C3 to C6)cycloalky(Ci to C6)alkyl, such as, for example, (C3 to C6)cycloalky(Ci to C3)alkyl, such as, for example, (C3 to C6)cycloalky-methyl-, such as, for example, cyclopropyl-methyl- and cyclohexyl-methyl-), and in one example, R44 is H; and Each R46 is independently selected from the group consisting of: H, alkyl (e.g., Ci to C6 alkyl, such as, for example, Ci to C3 alkyl, such as, for example, methyl, ethyl and i-propyl), cycloalkyl (e.g., C3 to C6 cycloalkyl, such as, for example, cyclopropyl and cyclohexyl), and cycloalkylalkyl (e.g., (C3 to C6)cycloalky(Ci to C6)alkyl, such as, for example, (C3 to Ce)cycloalky(Ci to C3)alkyl, such as, for example, (C3 to C6)cycloalky-methyl-, such as, for example, cyclopropyl-methyl- and cyclohexyl-methyl-), and in one example, each R46 is H. When R1 is a cycloalkyl group (i.e., R1 is R10 wherein R10 is cycloalkyl), examples of said cycloalkyl group include, but are limited to, cyclopropyl and cyclobutyl. When R1 is a heterocycloalkyl group (i.e., R1 is R10 wherein R10 is heterocycloalkyl), examples of said heterocycloalkyl group include, but are limited to, morpholinyl, pyrrolidinyl, piperidinyl and piperazinyl. When R1 is a heteroaryl group (i.e., R1 is R10 and R10 is heteroaryl), examples of said heteroaryl group include, but are not limited to, (a) unsubstituted heteroaryl, (b) heteroaryl substituted with 1 to 3 substituents independently selected from the group consisting of: -C(0)R38 (e.g., R38 is alkyl such as methyl) ,-NHR20 (e.g., -NHCH3), -OR20 (e.g., -OCH3), cycloalkyl (e.g., cyclopropyl) and halo (e.g., CI), (c) heteroaryl selected from the group consisting of: pyrrolyl, pyrazolyl, imidazolyl, furanyl, thienyl, thiazolyl, pyridyl, pyridyl N-O, and pyrimidinyl, RECIEVED IPONZ 22 AUGUST 2011 -73- (d) heteroaryl selected from the group consisting of: pyrrolyl, pyrazolyl, imidazolyl, furanyl, thienyl, thiazolyl, pyridyl, pyridyl N-O, and pyrimidinyl, wherein said heteroaryl is substituted with 1 to 3 substituents independently selected from the group consisting of: -C(0)R38 (e.g., R38 is alkyl such as methyl) ,-NHR20 (e.g., 5 -NHCH3), -OR20 (e.g., -OCH3), cycloalkyl (e.g., cyclopropyl) and halo (e.g., CI), and (e) heteroaryl selected from the group consisting of: thienyl substituted with -C(0)R38 (such as, for example, thienyl substituted with -C(0)CH3), thiazolyl substituted with -NHR such as, for example (thazolyl substituted with-NHCH3), pyridyl substituted with halo (such as, for example, pyridyl substituted with -CI), 10 pyridyl substituted with -OR20 (such as, for example, pyridyl substituted with methyl), and pyrimidinyl substituted with -OR20 (such as, for example, pyrimidinyl substituted with -OCH3). When R1 is a heteroarylalkyl group (i.e., R1 is R10 and R10 is heteroarylalkyl), examples of said heteroarylalkyl group include, but are not limited to, 15 (a) unsubstituted heteroarylalkyl- (b) heteroarylalkyl- substituted with 1 to 3 substituents independently selected from the group consisting of: -C(0)R38 (e.g., R38 is alkyl such as methyl), -NHR20 (e.g., -NHCH3), -OR20 (e.g., -OCH3), and halo (e.g., CI), (c) heteroarylalkyl- selected from the group consisting of: pyrrolylalkyl- (e.g., 20 pyrrolylCH2-), pyrazolylalkyl- (e.g., pyrazolylCH2-), imidazolylalkyl- (e.g., imdazolyl- CH2-), furanylalkyl- (e.g., furanylCH2-), thienylalkyl- (e.g., thienylCH2-), thiazolylalkyl-(e.g., thiazolylCH2-), pyridylalkyl- (e.g., pyridylCH2-), pyridyl N-0 alkyl- (e.g., pyridyl(N-0)CH2-), and pyrimidinylalkyl- (e.g., pyrimidinylCH2-), (d) heteroarylalkyl- selected from the group consisting of: pyrrolylalkyl- (e.g., 25 pyrrolylCH2-), pyrazolylalkyl- (e.g., pyrazolylCH2-), imidazolylalkyl- (e.g., imdazolylCH2- ), furanylalkyl- (e.g., furanylCH2-), thienylalkyl- (e.g., thienylCH2-), thiazolylalkyl- (e.g., thiazolylCH2-), pyridylalkyl- (e.g., pyridylCH2-), pyridyl N-O alkyl- (e.g., pyridyl(N-0)CH2-), and pyrimidinylalkyl- (e.g., pyrimidinylCH2-), wherein said heteroaryl is substituted with 1 to 3 substituents independently selected from the group consisting 30 of: -C(0)R38 (e.g., R38 is alkyl such as methyl) ,-NHR20 (e.g., -NHCH3), -OR20 (e.g., -OCH3), and halo (e.g., CI), and (e) heteroarylalkyl- selected from the group consisting of: thienylalkyl-substituted with a -C(0)R20 group (such as, for example, thienylCH2- substituted with -C(0)CH3), thiazolylalkyl- substituted with-NHR20 such as, for example (thazolylCH2- RECIEVED IPONZ 22 AUGUST 2011 -74- substituted with-NHCH3), pyridylalkyl- substituted with halo (such as, for example, pyridylCH2- substituted with -CI), pyridylalkyl- substituted with -OR20 (such as, for example, pyridylCH2- substituted with methyl), and pyrimidinylalky- substituted with-OR20 (such as, for example, pyrimidinylCH2- substituted with -OCH3). 5 When R1 is an aryl group (i.e., R1 is R10 and R10 is aryl), examples of said aryl group include, but are not limited to, phenyl and naphthyl, and preferably phenyl. When R1 is an arylalkyl group (i.e., R1 is R10 and R10 is arylalkyl), examples of said arylalkyl group include, but are not limited to, -(C(R30)2)nphenyl (e.g., -(CH2)nphenyl), wherein in one example said arylalkyl- is -(C(R30)2)nphenyl wherein n 10 is 1, and in another example said arylalkyl- is -(CH2)nphenyl wherein n is 1 (i.e., said arylalkyl- is benzyl). When R1 is a substituted arylalkyl group (i.e., R1 is R10 and R10 is a substituted arylalkyl), examples of said substituted arylalkyl group include, but are not limited to, -(C(R30)2)nsubstituted phenyl (e.g., -(CH2)nsubstituted phenyl), wherein in one 15 example said substituted arylalkyl- is -(C(R30)2)n substituted phenyl wherein n is 1, and in another example said substituted arylalkyl- is -(CH2)nsubstituted phenyl wherein n is 1 (i.e., said substituted arylalkyl- is substituted benzyl), wherein the aryl moiety of said substituted arylalkyl is substituted with 1 to 3 substituents independently selected from the group consisiting of: halo (e.g., F, CI and Br), -CF3, and -OR20 (e.g., -OCH3). 20 Those skilled in the art will appreciate that when Q1 is aryl, substituted aryl, heteroaryl or substituted heteroaryl the two carbon atoms common to the two fused rings are not substituted. Thus, there is no R3 and no R4 groups in 2.9 when Q1 is aryl, substituted aryl, heteroaryl or substituted heteroaryl. There is no R3 and no R4 25 groups in 2.10 when Q1 fused to the R3 and R4 positions is aryl, substituted aryl, heteroaryl or substituted heteroaryl. There is no R6 and no R7 groups in 2.10 when Q1 fused to the R6 and R7 positions is aryl, substituted aryl, heteroaryl or substituted heteroaryl. There is no R3 and no R4 groups in 2.11 when Q1 fused to the R3 and R4 positions is aryl, substituted aryl, heteroaryl or substituted heteroaryl. There is no R3 30 and no R4 groups in 2.13 when Q1 fused to the R3 and R4 positions is aryl, substituted aryl, heteroaryl or substituted heteroaryl. There is no R3 and no R4 groups in 2.14 when Q1 fused to the R3 and R4 positions is aryl, substituted aryl, heteroaryl or substituted heteroaryl. There is no R3 and no R4 groups in 2.15 when Q1 fused to the R3 and R4 positions is aryl, substituted aryl, heteroaryl or substituted heteroaryl. RECIEVED IPONZ 22 AUGUST 2011 -75- 10 15 There is no R6 and no R7 groups in 2.15 when Q1 fused to the R3 and R4 positions is aryl, substituted aryl, heteroaryl or substituted heteroaryl. In one embodiment of the compounds of formula 1.0, z is 1. Thus, in this embodiment the compounds of formula 1.0 have the formula 1.0A1: In another embodiment of the compounds of formula 1.0, z is 1 and R36 is H. Thus, in this embodiment the compounds of formula 1.0 have the formula 1 .OA: In another embodiment of the compounds of formula 1.0, Z is 1 and and R is -OCH3. In another embodiment of the compounds of formula 1.0, z is 1, and each R35 is independently selected from the group consisting of: H, methyl, ethyl, i-propyl and propyl (e.g., one R35 is H and the other is methyl, or both R35 substituents are methyl, or preferably both R35 substitutents are H). In another embodiment of the compounds of formula 1.0, z is 1, each R35 is independently selected from the group consisting of: H, methyl, ethyl, i-propyl and propyl (e.g., one R35 is H and the other is methyl, or both R35 substituents are methyl, or preferably both R35 substitutents are H), and R36 is selected from the group consisting of: H, methyl, ethyl and propyl. In another embodiment of the compounds of formula 1.0, z is 1, each R35 is independently selected from the group consisting of: H, methyl, ethyl, i-propyl and propyl (e.g., one R35 is H and the other is methyl, or both R35 substituents are methyl, or preferably both R35 substitutents are H), and R36 is selected from the group consisting of; H and methyl. RECIEVED IPONZ 22 AUGUST 2011 15 -76- ln another embodiment of the compounds of formula 1.0, z is 1, each R35 is independently selected from the group consisting of: H, methyl, ethyl, i-propyl and propyl (e.g., one R35 is H and the other is methyl, or both R35 substituents are methyl, or preferably both R35 substitutents are H), and R36 is: H. In another embodiment of the compounds of formula 1.0, each R35 is H. Thus, in this embodiment the compounds of formula 1.0 have the formula 1.0B1: r8 (1.0B1) In another embodiment of the compounds of formula 1.0, each R35 is H and R36 is H. Thus, in this embodiment the compounds of formula 1.0 have the formula 10 1,0B: r8 (1.0B) In another embodiment of the compounds of formula 1.0, z is preferably 1 and each R35 is preferably H. Thus, in this embodiment the compounds of formula 1.0 have the formula 1.0C1: r8 (1.0C1) In another embodiment of the compounds of formula 1.0, z is preferably 1, R35 is preferably H, ar 1.0 have the formula 1,0C: each R35 is preferably H, and R36 is H. Thus, preferably the compounds of formula RECIEVED IPONZ 22 AUGUST 2011 -77 R 10 r1 Another embodiment of this invention is directed to compounds of formula 1.0 having the formula 1.1 A: r8 o. o. y1_Y2 n' o (1.0C) o <11A) r1 Another embodiment of this invention is directed to compounds of formula 1.0 having the formula 1.1: r8 ov o 7 wXi X (1-1) H?A_YrM 4 ^ N^/ r1 wherein all substituents are as defined for formula 1.0. Another embodiment of this invention is directed to compounds of formulas 1.0 and 1.1A wherein Y1, Y2, and Y3 are -CH=. Thus, one embodiment of this invention is directed to compounds of formula 1.2A: (1.2A) 15 Another embodiment of this invention is directed to compounds of formulas 1.0 and 1.1 wherein Y1, Y2, and Y3 are -CH=. Thus, one embodiment of this invention is directed to compounds of formula 1.2: RECIEVED IPONZ 22 AUGUST 2011 -78- q (1.2) wherein all substitutents are as defined for formula 1.0. Another embodiment of this invention is directed to compounds of formula 1.0 having the formula 1.3A: Another embodiment of this invention is directed to compounds of formula 1.0 having the formula 1.3: wherein all substituents are as defined for formula 1.0. Examples of Q include, but are not limited to: moieties 2.1, 2.2, 2.3., 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 2.10, 2.11, 2.14, or 2.15 wherein each R3, R4, R6, and R7 is independently selected from the group consisting of: H and alkyl (e.g., Ci to C6 alkyl, such as, for example methyl). Examples of Q also include, but are not limited to: moieties 2.1, 2.2, 2.3., 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 2.10, 2.11, 2.14, or 2.15 wherein each R3, R4, R6, and R7 is H. Examples of Q also include, but are not limited to: moieties 2.17, 2.18, 2.19, 2.20 and 2.21 wherein each R3, R4, R6, and R7 is independently selected from the group consisting of: H and alkyl (e.g., Ci to C6 alkyl, such as, for example methyl). Examples of Q also include, but are not limited to: moieties 2.17, 2.18, 2.19, 2.20 and 2.21 wherein each R3, R4, R6, and R7 is H. (1.3A) RECIEVED IPONZ 22 AUGUST 2011 -79- Examples of Q include, but are not limited to: moieties 2.12, 2.13, or 2.16 wherein each R3, R4, and R7 is independently selected from the group consisting of: H and alkyl (e.g., Ci to C6 alkyl, such as, for example methyl). Examples of Q also include, but are not limited to: moieties 2.12, 2.13, or 2.16 5 wherein each R3, R4, and R7 is H. Examples of Q include, but are not limited to: moiety 2.22 wherein each R3, R4, and R7 is independently selected from the group consisting of: H and alkyl (e.g., Ci to C6 alkyl, such as, for example methyl). Examples of Q also include, but are not limited to: moiety 2.22 wherein each 10 R3, R4, and R7 is H. Thus, in one example of Q, Q is moiety 2.1 wherein each R3, R4, R6, and R7 is independently selected from the group consisting of: H and alkyl (e.g., C-i to C6 alkyl, such as, for example methyl). In another example of Q, Q is moiety 2.1 wherein each R3, R4, R6, and R7 is 15 independently selected from the group consisting of: H and methyl. In another example of Q, Q is moiety 2.1 wherein each R3, R4, R6, and R7 is H. In another example of Q, Q is moiety 2.2 wherein each R3, R4, R6, and R7 is independently selected from the group consisting of: H and alkyl (e.g., Ci to C6 alkyl, such as, for example methyl). 20 In another example of Q, Q is moiety 2.2 wherein each R3, R4, R6, and R7 is independently selected from the group consisting of: H and methyl. In another example of Q, Q is moiety 2.2 wherein each R3, R4, R6, and R7 is H. In another example of Q, Q is moiety 2.3 wherein each R3, R4, R6, and R7 is independently selected from the group consisting of: H and alkyl (e.g., Ci to C6 alkyl, 25 such as, for example methyl). In another example of Q, Q is moiety 2.3 wherein each R3, R4, R6, and R7 is independently selected from the group consisting of: H and methyl. In another example of Q, Q is moiety 2.3 wherein each R3, R4, R6, and R7 is H. In another example of Q, Q is moiety 2.4 wherein each R3, R4, R6, and R7 is 30 independently selected from the group consisting of: H and alkyl (e.g., Ci to C6 alkyl, such as, for example methyl). In another example of Q, Q is moiety 2.4 wherein each R3, R4, R6, and R7 is independently selected from the group consisting of: H and methyl. In another example of Q, Q is moiety 2.4 wherein each R3, R4, R6, and R7 is H. RECIEVED IPONZ 22 AUGUST 2011 -80- ln another example of Q, Q is moiety 2.5 wherein each R3, R4, R6, and R7 is independently selected from the group consisting of: H and alkyl (e.g., Ci to C6 alkyl, such as, for example methyl). In another example of Q, Q is moiety 2.5 wherein each R3, R4, R6, and R7 is 5 independently selected from the group consisting of: H and methyl. In another example of Q, Q is moiety 2.5 wherein each R3, R4, R6, and R7 is H. In another example of Q, Q is moiety 2.6 wherein each R3, R4, R6, and R7 is independently selected from the group consisting of: H and alkyl (e.g., to C6 alkyl, such as, for example methyl). 10 In another example of Q, Q is moiety 2.6 wherein each R3, R4, R6, and R7 is independently selected from the group consisting of: H and methyl. In another example of Q, Q is moiety 2.7 wherein each R3, R4, R6, and R7 is independently selected from the group consisting of: H and alkyl (e.g., Ci to C6 alkyl, such as, for example methyl). 15 In another example of Q, Q is moiety 2.7 wherein each R3, R4, R6, and R7 is independently selected from the group consisting of: H and methyl. In another example of Q, Q is moiety 2.7 wherein each R3, R4, R6, and R7 is H. In another example of Q, Q is moiety 2.8 wherein each R3, R4, R6, and R7 is independently selected from the group consisting of: H and alkyl (e.g., Ci to C6 alkyl, 20 such as, for example methyl). In another example of Q, Q is moiety 2.8 wherein each R3, R4, R6, and R7 is independently selected from the group consisting of: H and methyl. In another example of Q, Q is moiety 2.8 wherein each R3, R4, R6, and R7 is H. In another example of Q, Q is moiety 2.9 or 2.10 wherein each R3, R4, R6, and 25 R7 is independently selected from the group consisting of: H and alkyl (e.g., Ci to C6 alkyl, such as, for example methyl). In another example of Q, Q is moiety 2.9 or 2.10 wherein each R3, R4, R6, and R7 is independently selected from the group consisting of: H and methyl. In another example of Q, Q is moiety 2.9 or 2.10 wherein each R3, R4, R6, and 30 R7 is H. In another example of Q, Q is moiety 2.11 wherein each R3, R4, R6, and R7 is independently selected from the group consisting of: H and alkyl (e.g., to C6 alkyl, such as, for example methyl). RECIEVED IPONZ 22 AUGUST 2011 -81 - In another example of Q, Q is moiety 2.11 wherein each R3, R4, R6, and R7 is independently selected from the group consisting of: H and methyl. In another example of Q, Q is moiety 2.11 wherein each R3, R4, R6, and R7 is H. 5 In another example of Q, Q is moiety 2.12 or 2.13 wherein each R3, R4, and R7 is independently selected from the group consisting of: H and alkyl (e.g., Ci to C6 alkyl, such as, for example methyl). In another example of Q, Q is moiety 2.12 or 2.13 wherein each R3, R4, and R7 is independently selected from the group consisting of: H and methyl. 10 In another example of Q, Q is moiety 2.12 or 2.13 wherein each R3, R4, and R7 is H. In another example of Q, Q is moiety 2.14 or 2.15 wherein each R3, R4, R6, and R7 is independently selected from the group consisting of: H and alkyl (e.g., Ci to C6 alkyl, such as, for example methyl). 15 In another example ofQ, Q is moiety 2.14 or. 2.15 wherein each R3, R4, R6, and R7 is independently selected from the group consisting of: H and methyl. In another example of Q, Q is moiety 2.14 or 2.15 wherein each R3, R4, R6, and R7 is H. In another example of Q, Q is moiety 2.16 wherein each R3, R4, and R7 is H. 20 In another example of Q, Q is moiety 2.17 wherein each R3, R4, R6, and R7 is independently selected from the group consisting of: H and alkyl (e.g., Ci to C6 alkyl, such as, for example methyl). In another example of Q, Q is moiety 2.17 wherein each R3, R4, R6, and R7 is independently selected from the group consisting of: H and methyl. 25 In another example of Q, Q is moiety 2.17 wherein each R3, R4, R6, and R7 is H. In another example of Q, Q is moiety 2.18 wherein each R3, R4, R6, and R7 is independently selected from the group consisting of: H and alkyl (e.g., C-i to C6 alkyl, such as, for example methyl). 30 In another example of Q, Q is moiety 2.18 wherein each R3, R4, R6, and R7 is independently selected from the group consisting of: H and methyl. In another example of Q, Q is moiety 2.18 wherein each R3, R4, R6, and R7 is H. RECIEVED IPONZ 22 AUGUST 2011 -82- ln another example of Q, Q is moiety 2.19 wherein each R3, R4, R6, and R7 is independently selected from the group consisting of: H and alkyl (e.g., Ci to C6 alkyl, such as, for example methyl). In another example of Q, Q is moiety 2.19 wherein each R3, R4, R6, and R7 is 5 independently selected from the group consisting of: H and methyl. In another example of Q, Q is moiety 2.19 wherein each R3, R4, R6, and R7 is H. In another example of Q, Q is moiety 2.20 wherein each R3, R4, R6, and R7 is independently selected from the group consisting of: H and alkyl (e.g., Ci to C6 alkyl, 10 such as, for example methyl). In another example of Q, Q is moiety 2.20 wherein each R3, R4, R6, and R7 is independently selected from the group consisting of: H and methyl. In another example of Q, Q is moiety 2.20 wherein each R3, R4, R6, and R7 is H. .15 In another example of Q, Q is moiety 2.21 wherein each R3, R4, R6, and R7 is independently selected from the group consisting of: H and alkyl (e.g., C-i to C6 alkyl, such as, for example methyl). In another example of Q, Q is moiety 2.21 wherein each R3, R4, R6, and R7 is independently selected from the group consisting of: H and methyl. 20 In another example of Q, Q is moiety 2.21 wherein each R3, R4, R6, and R7 is H. In another example of Q, Q is moiety 2.22 wherein each R3, R4, and R7 is independently selected from the group consisting of: H and alkyl (e.g., Ci to C6 alkyl, such as, for example methyl). 25 In another example of Q, Q is moiety 2.22 wherein each R3, R4, and R7 is independently selected from the group consisting of: H and methyl. In another example of Q, Q is moiety 2.22 wherein each R3, R4, and R7 is H. 30 (i.e., each R isHandwisI). RECIEVED IPONZ 22 AUGUST 2011 -83- Another example of the Q substituent 2.3 is: (i.e., each R isHandwisI). Another example of the Q substitutent 2.3 is: 5 (2.3C) (i.e., each R24 is H and w is 1). An example of the Q substituent 2.4 is: (i.e., each R24 is H and w is 1). 10 Another example of the Q substituent 2.4 is: (i.e., each R24 is H and w is 1). Another example of the Q substituent 2.4 is: RECIEVED IPONZ 22 AUGUST 2011 10 (2.4C) (i.e., each R24 is H and w is 1). An example of the Q substituent 2.5 is: R7 .R7 r° 5 (i.e., each R24 is H and w is 1). Another example of the Q substituent 2.5 is: j r7 r7 an r6 rl rs r4 r4 (2.5B) (i.e., each R24 is H and w is 1). Another example of the Q substituent 2.5 is: r7 r7 24 (i.e., each R isHandwisI). An example of the Q substituent 2.6 is: \ n SRS (2.6A) An example of the Q substituent 2.7 is: RECIEVED IPONZ 22 AUGUST 2011 -85- {2.1k) (i.e., each R24 is H and w is 1). An example of the Q substituent 2.7 is: (2.7B) 5 (i.e., each R24 is H and w is 1). An example of the Q substituent 2.7 is: (2.7C) (i.e., each R24 is H and w is 1). An example of the Q substituent 2.8 is: 10 (2.8A) (i.e., each R24 is H and w is 1). Another example of the Q substituent 2.8 is: (2.8B) RECIEVED IPONZ 22 AUGUST 2011 -86- each R24 is H and w is 1). RECIEVED IPONZ 22 AUGUST 2011 -87 - Another example of the Q substituent 2.8 is: rI -R7 n' ,n, R r- •r5 r4 r4 (2.8C) (i.e., each R24 is H and w is 1). Another example of the Q substituent 2.3 is: \ r5 (2.3A1) Another example of the Q substituent 2.3 is: / tn R (2.3B1) Another example of the Q substituent 2.3 is: 10 VN<? "R (2.3C1) Another example of the Q substituent 2.4 is: \ r5 (2.4A1) Another example of the Q substituent 2.4 is: \ r5 (2.4B1) RECIEVED IPONZ 22 AUGUST 2011 -88- Another example of the Q substituent 2.4 is: 'R (2.4C1) Another example of the Q substituent 2.5 is: r5 (2.5A1) Another example of the Q substituent 2.5 is: n (2.5B1) rb Another example of the Q substituent 2.5 is: n' 10 rb (2.5C1) Another example of the Q substituent 2.7 is: (2.7A1) Another example of the Q substituent 2.7 is: v.. (2.7B1) Another example of the Q substituent 2.7 is: RECIEVED IPONZ 22 AUGUST 2011 -89 "n <? ,n (2.7C1) Another example of the Q substituent 2.8 is r5 Another example of the Q substituent 2.8 is: (2.8B1) Another example of the Q substituent 2.8 is: n UuiU N r5 (2.8C1) Another example of the Q substitutent is the piperazine ring: N substituted with one or two substituents independently selected from the group consisting of R3 groups, provided that said one or two substitutents are not H. In one embodiment said substituents are selected from the group consisting of alkyl groups (e.g., Ci to C6 alkyl, e.g., methyl). In another embodiment there is one substituent on said piperazine ring. In another embodiment there is one substituent on said piperazine ring and said substituent is methyl. Another example of the Q substituent is the piperazine ring: RECIEVED IPONZ 22 AUGUST 2011 -90- Another example of the Q substitutent is the piperidine ring: substituted with one or two substituents independently selected from the group 5 consisting of R3 groups, provided that said one or two substitutents are not H. In one embodiment said substituents are selected from the group consisting of alkyl groups (e.g., Cm to C6 alkyl, e.g., methyl). In another embodiment there is one substituent on said piperidine ring. In another embodiment there is one substituent on said piperidine ring and said substituent is methyl. 10 In one example of the Q substituent 2.16 15 (2.16A) (i.e., Q1 is pyridyl, and each R3, R4 and R7 is H). RECIEVED IPONZ 22 AUGUST 2011 -91 - In another example, the Q substituent 2.16 is 2.16A1: -N (2.16A1) Another example of the Q substitutent 2.16 is 2.16B: (2.16B) 5 (i.e., Q1 is phenyl, and each R3, R4 and R7 is H). When the Q substitutent comprises two Q1 rings, each Q1 ring is independently selected. Generally, the Q1 cycloalkyl rings and the Q1 substituted cycloalkyl rings comprise 5 to 7 ring carbons. In general, the heterocycloalkyl Q1 rings and the substituted heterocycloalky Q1 rings comprise 5 to 7 ring carbons and comprise 1 to 3 10 (generally 1 or 2, or generally 1) ring heteroatoms selected from the group consisting of: O, N and S. In general, the heteroaryl Q1 rings and the substituted heteroaryl Q1 rings comprise 5 to 7 ring carbons and comprise 1 to 3 (generally 1 or 2, or generally 1) ring heteroatoms selected from the group consisting of: O, N and S. Examples of the Q1 rings include, but are not limited to: piperidinyl, piperazinyl, pyranyl, pyrrolidinyl, 15 morpholinyl, thiomorpholinyl, pyridyl, pyrimidinyl, pyrrolyl, pyrazolyl, furanyl, thienyl, thiazolyl, imidazolyl, cyclopentyl, cyclohexyl and cycloheptyl. Examples of the Q1 rings also include, but are not limited to: substituted piperidinyl, substituted piperazinyl, substituted pyranyl, substituted pyrrolidinyl, substituted morpholinyl, substituted thiomorpholinyl, substituted pyridyl, substituted pyrimidinyl, substituted 20 pyrrolyl, substituted pyrazolyl, substituted furanyl, substituted thienyl, substituted thiazolyl, substituted imidazolyl, substituted cyclopentyl, substituted cyclohexyl and substituted cycloheptyl wherein said substituted Q1 rings are substituted with 1 to 3 10 substitutents selected from the R moieties. Generally, the Q2 cycloalkyl rings and the Q2 substituted cycloalkyl rings 25 comprise 5 to 7 ring carbons. In general, the heterocycloalkyl Q2 rings and the substituted heterocycloalky Q1 rings comprise 5 to 7 ring carbons and comprise 1 to 3 RECIEVED IPONZ 22 AUGUST 2011 -92- (generally 1 or 2, or generally 1) ring heteroatoms selected from the group consisting of: O, N and S. Examples of the Q2 rings include, but are not limited to: piperidinyl, piperazinyl, pyranyl, pyrrolidinyl, cyclopentyl, cyclohexyl and cycloheptyl. Examples of the Q2 5 rings also include, but are not limited to: substituted piperidinyl, substituted piperazinyl, substituted pyranyl, substituted pyrrolidinyl, substituted morpholinyl, substituted thiomorpholinyl, substituted cyclopentyl, substituted cyclohexyl and substituted cycloheptyl wherein said substituted Q1 rings are substituted with 1 to 3 substitutents selected from the R10 moieties. 10 In one example the Q substituent 2.17 is: (2.17A) wherein R5A is halo. Another example of the Q substituent 2.17 is: f 15 (2.17B) Another example of the Q substituent 2.17 is: oh (2.17C) Another example of the Q substituent 2.17 is: (2.17D) RECIEVED IPONZ 22 AUGUST 2011 -93 - wherein R5A is alkoxy, i.e., -O-^ to C6)alkyl, such as, for example, -0-(C1 to C3)alkyl, or -0-(Ci to C2)alkyl. Another example of the Q substituent 2.17 is: och3 (2.17E) 5 Examples of R1 for the compounds of this invention (e.g., compounds of formulas 1.0, 1.0A1, 1.0B1, 1.0C1, 1.1, 1.1 A, 1.2, 1.2A, 1.3 and 1.3A) include, but are not limited to: js—ch2-n—c—<^\ ' —ch2~n—s(0)2ch3' \—ch2-n—c—n—ch(ch3)2 ■ ch2ch3 o o 10 o S h 11 5 h —ch2 n c—n—c2h5 , ch2-n-c-ch3 , o h -ch2-n—c—ch(ch3)2 ii o 5—c—n f s cf3 _ <—cooh <—ch3 <—ch2oh , <—c=c— ch3 £— ch2nh2 15 S b S SS S H S h s h £ h £> h / \ s h -N—C—<C|, |-n-c-c3h7, |-n-c-ch3> 5-n-c-^ h ^-n-c_nh2) o o o o o 5 h h >—N—C—N s O \\ // h h s h -n-c—n-c2h5 , s_n—s-ch3 II < 02 ' O ^ 20 RECIEVED IPONZ 22 AUGUST 2011 -94- nh nh c c. <■ ii h p ii s s < -c—n-oh , 5—c-oh > S—C—o—CH3 > 5 c—nh? ' S-c-nh-(ch2)2-0-ch3 < s ii s || s ii * o « » o c O O 5 'J- H " -c-nh-(ch2)2-oh - -c—nh2 ' c—n— c—c—nh2 O h ch(ch3)2 h -c—n—ch3 ii O h -C_N_C H ii 9 O -c-n-ch(ch3)2 o h -c—n—ch2 ii 2 O -b -c—n ii O h M 1/ I n - c—n—ch2—^ ^—c—n—^ \ ^—c—n—<^j > o \=/ O \==/ o HO^ -c—n—ch—\ . n A=/ HO^ H I //~\ -c—n-ch—(' x> H X=/ °^C--0^CH3 h i -c—n—ch 10 O^. ,0^ ^ch3 h i -c—N—ch O -c-nh-ch2-ch2-0-ch3 O -c-nh-ch2-ch2-oh O RECIEVED IPONZ 22 AUGUST 2011 -95- lAAAO JVW OWV y/xn/xr c=0 h3c N 'S \ / N—t / s n" hn' ^CH3 s' xn / t) / " vAA/VO JVUV v/WVI "AAA/1 v/W/V och. ^ N ^ ^ ^ n ch3 , n cf3 , 0ch3 vAAAT A/VP ch3 vAAA/1 ch3 ch3 ij\j\r\n ch3 ^ n oh /• Xl ^o , jwv v/vwr> A N<^N ' T ' 0ch3 10 och3 . n ii C^ /OH N h RECIEVED IPONZ 22 AUGUST 2011 -96 och3 ^CN c=0 I nh I c2h4 n(ch3)2 c=0 I nh I c2h4 nh2 f ■ CI \ ch-. A no2 , o2n f3c (h3c)2hc RECIEVED IPONZ 22 AUGUST 2011 -97 och, och, ch(ch3)2 *och3 cf3 hn ch3 0^C^nh^CH2CH2CH3 hn^c^CH3 ii o jvw1 o" V—o no2 "f, f' r^\r"F f^T) r^Tl cf3 RECIEVED IPONZ 22 AUGUST 2011 -98 och3 ch3 juwv o "ch2ch3 ch3 n och3 10 ch3 H2 ■c-sr !aaaa/ cf3 RECIEVED IPONZ 22 AUGUST 2011 -99- R1, in one embodiment of this invention, is aryl (e.g., phenyl). R1, in one embodiment of this invention is substituted aryl, such as, R1, in another embodiment of this invention, is heteroaryl (e.g., in one embodiment R1 is pyridyl N-oxide, and in another embodiment R1 is pyridyl, such as ^^On) . R1, in one embodiment of this invention, is substituted heteroaryl (e.g., 10 substituted pyridyl). R1, in one embodiment of this invention, is substituted heteroaryl (e.g., 15 Examples of R5 for the compounds of this invention (e.g., compounds of formulas 1.0, 1.0A1, 1.0B1, 1.0C1, 1.1, 1.1 A, 1.2, 1.2A, 1.3 and 1.3A) include but are not limited to: 20 RECIEVED IPONZ 22 AUGUST 2011 -100 N . n nh2 . / /ch2ch3 o c ch2ch3 ii o A-s / *-Q , S-\ , Br 10 RECIEVED IPONZ 22 AUGUST 2011 -101 n f~ 'N Br , F , ch2 -cec \\ // -CEC H » » h2 -c-c=ch2 h -c—ch3 II O n nch2ch3 In another embodiment of this invention, R is selected from the group consisting of: RECIEVED IPONZ 22 AUGUST 2011 In another embodiment of this invention, R5 is selected from the group consisting of: and 10 In another embodiment of this invention, R is: In another embodiment of this invention, R5 is: A 15 In another embodiment of this invention, R5 is: RECIEVED IPONZ 22 AUGUST 2011 -103- R2, in one embodiment of this invention, is -(CH2)mR11, wherein R11 is -OR10. R2, in another embodiment of this invention, is -(CH2)mR11, wherein R11 is -OR10, and R10 is H or alkyl. R2, in another embodiment of this invention, is -(CH2)mR11, wherein R11 is -OR10, and R10 alkyl (e.g., methyl). R2, in another embodiment of this invention, is -(CH2)mR11, wherein m is 1 and R11 is-OR10. R2, in another embodiment of this invention, is -(CH2)mR11, wherein m is 1, R11 is -OR10, and R10 is H or alkyl. R2, in another embodiment of this invention, is -(CH2)mR11, wherein m is 1, R11 is -OR10, and R10 alkyl. R2, in another embodiment of this invention, is -(CH2)mR11, wherein m is 1, R11 is -OR10, and R10 methyl (i.e., R2 is -CH2OCH3). R2, in another embodiment of this invention, is -OR23 wherein R23 is alkyl, and said alkyl is methyl (i.e., R2 is -OCH3). R2, in another embodiment of this invention, is alkynyl. An example of an alkynyl group is ethynyl: R2, in another embodiment of this invention, is alkenyl. An example of an alkenyl group is -CH2-CH=CH2. Preferably R2 is selected from the group consisting of: ethynyl, -OCH3, and -CH2OCH3. Additional examples of the R2 -(CH2)mR11 group include, but are not limited to -CH2OH, -CH2CN, -CH2OC2H5, -(CH2)3OCH3, -CH2F and -CH2-triazolyl, such as, Another example of an alkynyl group is propynyl: ^ H2 _ <—c—c—ch RECIEVED IPONZ 22 AUGUST 2011 -104- Additional examples of R2 include, but are not limited to, H, -CH2-morpholinyl, -SCH3, -OC2H5i -OCH(CH3)2, -CH2N(CH3)2, -CN, -CH(OH)CH3, -C(0)CH3i -CH2C=CCH3, -CH(CH3)2i -C(CH3)=CH2i -C(CH3)=NOCH3i -C(CH3)=NOH, -C(CH3)=NNHC(0)CH3, -NH2, -NHC(0)H, -NHCH3i -CH2-0-CH2-cyclopropyl, 5 -CH2-0-CHF2, -OCHF2, -CHF2, -CH2C(CH3)=CH3i -CH2CH2CH3i -N(CH3)2, -CH2CH3, -CF3i -CH=CH2, and -C(OH)(CH3)2. R3, in one embodiment of this invention, is independently selected from the group consisting of: H and alkyl. R3, in another embodiment of this invention, is independently selected from the 10 group consisting of: H and methyl. R3, in another embodiment of this invention, is H. R4, in one embodiment of this invention, R4 H. R4, in another embodiment of this invention, is selected from the group consisting of: H and alkyl. 15 R4, in another embodiment of this invention, is selected from the group consisting of: H and methyl. R6, in one embodiment of this invention, is R6 H. R7, in one embodiment of this invention, is independently selected from the group consisting of: H and alkyl. 20 R7, in another embodiment of this invention, is independently selected from the group consisting of: H and methyl. R7, in one embodiment of this invention, is H. R8, in one embodiment of this invention, is H. Y1, in one embodiment of this invention, is carbon. 25 Y2, in one embodiment of this invention, is carbon. Y3 in one embodiment of this invention, is carbon. Y1, Y2 and Y3, in one embodiment of this invention, are carbon. One embodiment of this invention is directed to a compound of formula 1.0, preferably a compound of formula 1.0C1 and more preferably a compound of formula 30 1.0C, (e.g., 1.1, 1.1 A, 1.2, 1.2A, 1.3 or 1.3A) wherein substituent Q is 2.16, and each R3, R4, and R7 is independently selected from the group consisting of: H and methyl. One embodiment of this invention is directed to a compound of formula 1.0, preferably a compound of formula 1.0C1 and more preferably a compound of formula 1.0C, (e.g., 1.1, 1.1 A, 1.2, 1.2A, 1.3 or 1.3A) wherein substituent Q is 2.16A, and RECIEVED IPONZ 22 AUGUST 2011 -105- each R3, R4, and R7 is independently selected from the group consisting of: H and methyl. One embodiment of this invention is directed to a compound of formula 1.0, preferably a compound of formula 1.0C1 and more preferably a compound of formula 5 1.0C, (e.g., 1.1, 1.1 A, 1.2, 1.2A, 1.3 or 1.3A) wherein substituent Q is 2.16B, and each R3, R4, and R7 is independently selected from the group consisting of: H and methyl. One embodiment of this invention is directed to a compound of formula 1.0, preferably a compound of formula 1.0C1 and more preferably a compound of formula 10 1.0C, (e.g., 1.1, 1.1A, 1.2, 1.2A, 1.3 or 1,3A) wherein substituent Q is 2.16, and each R3, R4, and R7 is H. One embodiment of this invention is directed to a compound of formula 1.0, preferably a compound of formula 1.0C1 and more preferably a compound of formula 1.0C, (e.g., 1.1, 1.1 A, 1.2, 1.2A, 1.3 or 1.3A) wherein substituent Q is 2.16A, and 15 each R3, R4, and R7 is H. One embodiment of this invention is directed to a compound of formula 1.0, preferably a compound of formula 1.0C1 and more preferably a compound of formula 1.0C, (e.g., 1.1,1.1 A, 1.2, 1.2A, 1.3 or 1.3A) wherein substituent Q is 2.16B, and each R3, R4, and R7 is H. 20 The compounds of this invention inhibit the activity of ERK1 and ERK2 Thus, also described is a method of inhibiting ERK in mammals, especially humans, by the administration of an effective amount (e.g., a therapeutically effective amount) of one or more (e.g., one) compounds of this invention. The administration of the compounds of this invention to patients, to inhibit ERK1 and/or ERK2, is useful in the 25 treatment of cancer. In any of the methods of treating cancer described herein, unless stated otherwise, the methods can optionally include the administration of an effective amount of one or more (e.g., 1, 2 or 3, or 1 or 2, or 1) chemotherapeutic agents. The chemotherapeutic agents can be administered currently or sequentially with the 30 compounds of this invention. The uses of the invention similarly contemplate the manufacture of medicaments comprising a chemotherapeutic agent, or in a form for administration with a chemotherapeutic agent. The methods of treating cancer described herein include methods wherein a combination of drugs (i.e., compounds, or pharmaceutically active ingredients, or RECIEVED IPONZ 22 AUGUST 2011 -106 - pharmaceutical compositions) are used (i.e., the methods of treating cancer include combination therapies). Similarly, the uses of the invention encompass combinations useful in the methods described herein. Those skilled in the art will appreciate that the drugs are generally administered individually as a pharmaceutical composition. 5 The use of a pharmaceutical composition comprising more than one drug is within the scope of this invention. In any of the methods of treating cancer described herein, unless stated otherwise, the methods can optionally include the administration of an effective amount of radiation therapy. For radiation therapy, y-radiation is preferred. 10 Examples of cancers which may be treated by the methods described herein include, but are not limited to: (A) lung cancer (e.g., lung adenocarcinoma and non small cell lung cancer), (B) pancreatic cancers (e.g., pancreatic carcinoma such as, for example, exocrine pancreatic carcinoma), (C) colon cancers (e.g., colorectal carcinomas, such as, for example, colon adenocarcinoma and colon adenoma), (D) 15 myeloid leukemias (for example, acute myelogenous leukemia (AML), CML, and CMML), (E) thyroid cancer, (F) myelodysplastic syndrome (MDS), (G) bladder carcinoma, (H) epidermal carcinoma, (I) melanoma, (J) breast cancer, (K) prostate cancer, (L) head and neck cancers (e.g., squamous cell cancer of the head and neck), (M) ovarian cancer, (N) brain cancers (e.g., gliomas, such as glioma blastoma 20 multiforme), (O) cancers of mesenchymal origin (e.g., fibrosarcomas and rhabdomyosarcomas), (P) sarcomas, (Q) tetracarcinomas, (R) nuroblastomas, (S) kidney carcinomas, (T) hepatomas, (U) non-Hodgkin's lymphoma, (V) multiple myeloma, and (W) anaplastic thyroid carcinoma. Chemotherapeutic agents (antineoplastic agent) include but are not limited to: 25 microtubule affecting agents, alkylating agents, antimetabolites, natural products and their derivatives, hormones and steroids (including synthetic analogs), and synthetics. Examples of alkylating agents (including nitrogen mustards, ethylenimine derivatives, alkyl sulfonates, nitrosoureas and triazenes) include: Uracil mustard, Chlormethine, Cyclophosphamide (Cytoxan®), Ifosfamide, Melphalan, Chlorambucil, 30 Pipobroman, Triethylene-melamine, Triethylenethiophosphoramine, Busulfan, Carmustine, Lomustine, Streptozocin, Dacarbazine, and Temozolomide. Examples of antimetabolites (including folic acid antagonists, pyrimidine analogs, purine analogs and adenosine deaminase inhibitors) include: Methotrexate, RECIEVED IPONZ 22 AUGUST 2011 -107 - 5-Fluorouracil, Floxuridine, Cytarabine, 6-Mercaptopurine, 6-Thioguanine, Fludarabine phosphate, Pentostatine, and Gemcitabine. Examples of natural products and their derivatives (including vinca alkaloids, antitumor antibiotics, enzymes, lymphokines and epipodophyllotoxins) include: Vinblastine, Vincristine, Vindesine, Bleomycin, Dactinomycin, Daunorubicin, Doxorubicin, Epirubicin, Idarubicin, Paclitaxel (paclitaxel is a microtubule affecting agent and is commercially available as Taxol®), Paclitaxel derivatives (e.g. taxotere), Mithramycin, Deoxyco-formycin, Mitomycin-C, L-Asparaginase, Interferons (especially IFN-a), Etoposide, and Teniposide. Examples of hormones and steroids (including synthetic analogs) include: 17a-Ethinylestradiol, Diethylstilbestrol, Testosterone, Prednisone, Fluoxymesterone, Dromostanolone propionate, Testolactone, Megestrolacetate, Tamoxifen, Methylprednisolone, Methyl-testosterone, Prednisolone, Triamcinolone, Chlorotrianisene, Hydroxyprogesterone, Aminoglutethimide, Estramustine, Medroxyprogesteroneacetate, Leuprolide, Flutamide, Toremifene, and Zoladex. Examples of synthetics (including inorganic complexes such as platinum coordination complexes): Cisplatin, Carboplatin, Hydroxyurea, Amsacrine, Procarbazine, Mitotane, Mitoxantrone, Levamisole, and Hexamethylmelamine. Examples of other chemotherapeutics include: Navelbene, CPT-11, Anastrazole, Letrazole, Capecitabinbe, Reloxafine, and Droloxafine. A microtubule affecting agent (e.g., paclitaxel, a paclitaxel derivative or a paclitaxel-like compound), as used herein, is a compound that interferes with cellular mitosis, i.e., having an anti-mitotic effect, by affecting microtubule formation and/or action. Such agents can be, for instance, microtubule stabilizing agents or agents which disrupt microtubule formation. Microtubule affecting agents, useful in the methods described, and uses of this invention, are well known to those skilled in the art and include, but are not limited to: Allocolchicine (NSC 406042), Halichondrin B (NSC 609395), Colchicine (NSC 757), Colchicine derivatives (e.g., NSC 33410), Dolastatin 10 (NSC 376128), Maytansine (NSC 153858), Rhizoxin (NSC 332598), Paclitaxel (Taxol®, NSC 125973), Paclitaxel derivatives (e.g., Taxotere, NSC 608832), Thiocolchicine (NSC 361792), Trityl Cysteine (NSC 83265), Vinblastine Sulfate (NSC 49842), Vincristine Sulfate (NSC 67574), Epothilone A, Epothilone, Discodermolide (see Service, (1996) Science, 274:2009), Estramustine, Nocodazole, MAP4, and the like. Examples of such agents RECIEVED IPONZ 22 AUGUST 2011 -108 - are described in, for example, Bulinski (1997) J. Cell Sci. 110:3055-3064, Panda (1997) Proc. Natl. Acad. Sci. USA 94:10560-10564, Muhlradt (1997) Cancer Res. 57:3344-3346, Nicolaou (1997) Nature 387:268-272, Vasquez (1997) Mol. Biol. Cell. 8:973-985, and Panda (1996) J. Biol. Chem. 271:29807-29812. 5 Chemotherapeutic agents with paclitaxel-like activity include, but are not limited to, paclitaxel and paclitaxel derivatives (paclitaxel-like compounds) and analogues. Paclitaxel and its derivatives (e.g. Taxol and Taxotere) are available commercially. In addition, methods of making paclitaxel and paclitaxel derivatives and analogues are well known to those of skill in the art (see, e.g., U.S. Patent Nos: 5,569,729; 10 5,565,478; 5,530,020; 5,527,924; 5,508,447; 5,489,589; 5,488,116; 5,484,809; 5,478,854; 5,478,736; 5,475,120; 5,468,769; 5,461,169; 5,440,057; 5,422,364; 5,411,984; 5,405,972; and 5,296,506). More specifically, the term "paclitaxel" as used herein refers to the drug commercially available as Taxol® (NSC number: 125973). Taxol® inhibits eukaryotic 15 cell replication by enhancing polymerization of tubulin moieties into stabilized microtubule bundles that are unable to reorganize into the proper structures for mitosis. Of the many available chemotherapeutic drugs, paclitaxel has generated interest because of its efficacy in clinical trials against drug-refractory tumors, including ovarian and mammary gland tumors (Hawkins (1992) Oncology, 6: 17-23, 20 Horwitz (1992) Trends Pharmacol. Sci. 13: 134-146, Rowinsky (1990) J. Natl. Cane. Inst. 82: 1247-1259). Additional microtubule affecting agents can be assessed using one of many such assays known in the art, e.g., a semiautomated assay which measures the tubulin-polymerizing activity of paclitaxel analogs in combination with a cellular assay 25 to measure the potential of these compounds to block cells in mitosis (see Lopes (1997) Cancer Chemother. Pharmacol. 41:37-47). Generally, activity of a test compound is determined by contacting a cell with that compound and determining whether or not the cell cycle is disrupted, in particular, through the inhibition of a mitotic event. Such inhibition may be mediated 30 by disruption of the mitotic apparatus, e.g., disruption of normal spindle formation. Cells in which mitosis is interrupted may be characterized by altered morphology (e.g., microtubule compaction, increased chromosome number, etc.). Compounds with possible tubulin polymerization activity can be screened in vitro. For example, the compounds are screened against cultured WR21 cells RECIEVED IPONZ 22 AUGUST 2011 -109- (derived from line 69-2 wap-ras mice) for inhibition of proliferation and/or for altered cellular morphology, in particular for microtubule compaction. In vivo screening of positive-testing compounds can then be performed using nude mice bearing the WR21 tumor cells. Detailed protocols for this screening method are described by 5 Porter (1995) Lab. Anim. Sci., 45(2):145-150. Other methods of screening compounds for desired activity are well known to those of skill in the art. Typically such assays involve assays for inhibition of microtubule assembly and/or disassembly. Assays for microtubule assembly are described, for example, by Gaskin et al. (1974) J. Molec. Biol., 89: 737-758. U.S. 10 Patent No. 5,569,720 also provides in vitro and in vivo assays for compounds with paclitaxel-like activity. Thus, in the methods described, and uses of this invention wherein at least one chemotherapeutic agent is used, examples of said chemotherapeutic agents include those selected from the group consisting of: microtubule affecting agents, alkylating 15 agents, antimetabolites, natural products and their derivatives, hormones and steroids (including synthetic analogs), and synthetics. In the methods described, and uses of this invention wherein at least one chemotherapeutic agent is used, examples of said chemotherapeutic agents also include: (1) taxanes, (2) platinum coordinator compounds, (3) epidermal growth factor 20 (EGF) inhibitors that are antibodies, (4) EGF inhibitors that are small molecules, (5) vascular endolithial growth factor (VEGF) inhibitors that are antibodies, (6) VEGF kinase inhibitors that are small molecules, (7) estrogen receptor antagonists or selective estrogen receptor modulators (SERMs), (8) anti-tumor nucleoside derivatives, (9) epothilones, (10) topoisomerase inhibitors, (11)vinca alkaloids, (12) 25 antibodies that are inhibitors of aV(33 integrins, (13) folate antagonists, (14) ribonucleotide reductase inhibitors, (15) anthracyclines, (16) biologies; (17) inhibitors of angiogenesis and/or suppressors of tumor necrosis factor alpha (TNF-alpha) such as thalidomide (or related imid), (18) Bcr/abl kinase inhibitors, (19) MEK1 and/or MEK 2 inhibitors that are small molecules, (20) IGF-1 and IGF-2 inhibitors that are small 30 molecules, (21) small molecule inhibitors of RAF and BRAF kinases, (22) small molecule inhibitors of cell cycle dependent kinases such as CDK1, CDK2, CDK4 and CDK6, (23) alkylating agents, and (24) farnesyl protein transferase inhibitors (also know as FPT inhibitors or FTI (i.e., farnesyl transfer inhibitors)). RECIEVED IPONZ 22 AUGUST 2011 -110 - In the methods described, and uses of this invention wherein at least one chemotherapeutic agent is used, examples of such chemotherapeutic agents include: (1) taxanes such as paclitaxel (TAXOL®) and/or docetaxel (Taxotere®); (2) platinum coordinator compounds, such as, for example, carboplatin, cisplatin and oxaliplatin (e.g. Eloxatin); (3) EGF inhibitors that are antibodies, such as: HER2 antibodies (such as, for example trastuzumab (Herceptin®), Genentech, Inc.), Cetuximab (Erbitux, IMC-C225, ImClone Systems), EMD 72000 (Merck KGaA), anti-EFGR monoclonal antibody ABX (Abgenix), TheraCIM-h-R3 (Center of Molecular Immunology), monoclonal antibody 425 (Merck KGaA), monoclonal antibody ICR-62 (ICR, Sutton, England); Herzyme (Elan Pharmaceutical Technologies and Ribozyme Pharmaceuticals), PKI 166 (Novartis), EKB 569 (Wyeth-Ayerst), GW 572016 (GlaxoSmithKline), CI 1033 (Pfizer Global Research and Development), trastuzmab-maytansinoid conjugate (Genentech, Inc.), mitumomab (Imclone Systems and Merck KGaA) and Melvax II (Imclone Systems and Merck KgaA); (4) EGF inhibitors that are small molecules, such as, Tarceva (TM) (OSI-774, OSI Pharmaceuticals, Inc.), and Iressa (ZD 1839, Astra Zeneca); (5) VEGF inhibitors that are antibodies such as: bevacizumab (Genentech, Inc.), and IMC-1C11 (ImClone Systems), DC 101 (a KDR VEGF Receptor 2 from ImClone Systems); (6) VEGF kinase inhibitors that are small molecules such as SU 5416 (from Sugen, Inc), SU 6688 (from Sugen, Inc.), Bay 43-9006 (a dual VEGF and bRAF inhibitor from Bayer Pharmaceuticals and Onyx Pharmaceuticals); (7) estrogen receptor antagonists or selective estrogen receptor modulators (SERMs), such as tamoxifen, idoxifene, raloxifene, trans-2,3-dihydroraloxifene, levormeloxifene, droloxifene, MDL 103,323, and acolbifene (Schering Corp.); (8) anti-tumor nucleoside derivatives such as 5-fluorouracil, gemcitabine, capecitabine, cytarabine (Ara-C), fludarabine (F-Ara-A), decitabine, and chlorodeoxyadenosine (Cda, 2-Cda); (9) epothilones such as BMS-247550 (Bristol-Myers Squibb), and EP0906 (Novartis Pharmaceuticals); (10) topoisomerase inhibitors such as topotecan (Glaxo SmithKline), and Camptosar (Pharmacia); RECIEVED IPONZ 22 AUGUST 2011 -111 - (11) vinca alkaloids, such as, navelbine (Anvarand Fabre, France), vincristine and vinblastine; (12) antibodies that are inhibitors of aV|33 integrins, such as, LM-609 (see, Clinical Cancer Research, Vol. 6, page 3056-3061, August 2000, the disclosure of 5 which is incorporated herein by reference thereto); (13) folate antagonists, such as Methotrexate (MTX), and Premetrexed (Alimta); (14) ribonucleotide reductase inhibitors, such as Hydroxyurea (HU); (15) anthracyclines, such as Daunorubicin, Doxorubicin (Adriamycin), and 10 Idarubicin; (16) biologies, such as interferon (e.g., Intron-A and Roferon), pegylated interferon (e.g., Peg-lntron and Pegasys), and Rituximab (Rituxan, antibody used for the treatment of non-Hodgkin's lymphoma); (17) thalidomide (or related imid); 15 (18) Bcr/abl kinase inhibitors, such as, for example Gleevec (STI-571), AMN- 17, ON012380, SU11248 (Sunitinib) and BMS-354825 (19) MEK1 and/or MEK2 inhibitors, such as PD0325901 and Arry-142886 (AZD6244); (20) IGF-1 and IGF-2 inhibitors that are small molecules, such as, for example, 20 NVP-AEW541; (21) small molecule inhibitors of RAF and BRAF kinases, such as, for example, BAY 43-9006 (Sorafenib); (22) small molecule inhibitors of cell cycle dependent kinases such as CDK1, CDK2, CDK4 and CDK6, such as, for example, CYC202, BMS387032, and 25 Flavopiridol; (23) alkylating agents, such as, for example, Temodar® brand of temozolomide; (24) farnesyl protein transferase inhibitors, such as, for example: (a) Sarasar® brand of lonifarnib (i.e., 4-[2-[4-(3,10-dibromo-8-chloro-30 6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-£>]byridin-11-yl)-1-piperidinyl)-2-oxoethyl]-1-piperidinecarboxamide, see for example, U.S. 5,874,442 issued February 23, 1999, and U.S. 6,632,455 issued October 14, 2003 the disclosures of each being incorporated herein by reference thereto), RECIEVED IPONZ 22 AUGUST 2011 10 15 20 -112- (b) Zarnestra® brand of tipifarnib (i.e., (R)-6-amino[(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methyl]-4-(3-chlorophenyl )-1- methyl-2(1H)-quinolinone, see for example, WO 97/16443 published May 9, 1997 and U.S. 5,968,952 issued October 19, 1999, the disclosures of each being incorporated herein by reference thereto), and (see W097/30992 published August 28, 1997, U.S. 6,011,029 issued January 4, 2000, and U.S. 6,455,523, the disclosures of each being incorporated herein by reference thereto). The Bcr/abl kinase inhibitors, EGF receptor inhibitors, and HER-2 antibodies (EGF receptor inhibitors that are antibodies) described above are also known as signal transduction inhibitors. Therefore, chemotherapeutic agents, as used herein, include signal transduction inhibitors. Typical signal transduction inhibitors, that are chemotherapeutic agents, include but are not limited to: (i) Bcr/abl kinase inhibitors such as, for example, STI 571 (Gleevec), (ii) Epidermal growth factor (EGF) receptor inhibitor such as, for example, Kinase inhibitors (Iressa, OSI-774) and antibodies (Imclone: C225 [Goldstein et al. (1995), Clin Cancer Res. 1:1311-1318], and Abgenix: ABX-EGF) and (iii) HER-2/neu receptor inhibitors such as, for example, Herceptin® (trastuzumab). Methods for the safe and effective administration of most of these chemotherapeutic agents are known to those skilled in the art. In addition, their administration is described in the standard literature. For example, the administration of many of the chemotherapeutic agents is described in the "Physicians' Desk Reference" (PDR), e.g., 1996 edition (Medical Economics Company, Montvale, NJ 07645-1742, USA), the Physician's Desk Reference, 56th Edition, 2002 (published by Medical Economics company, Inc. Montvale, NJ 07645-1742), and the Physician's (c) Bristol-Myers Squibb 214662: N RECIEVED IPONZ 22 AUGUST 2011 -113 - Desk Reference, 57th Edition, 2003 (published by Thompson PDR, Montvale, NJ 07645-1742); the disclosures of which is incorporated herein by reference thereto. For example, the compound of formula 1.0 (e.g., a pharmaceutical composition comprising the compound of formula 1.0); can be administered orally (e.g., as a 5 capsule), and the chemotherapeutic agents can be administered intravenously, usually as an IV solution. The use of a pharmaceutical composition comprising more than one drug is within the scope of this invention. The compound of formula 1.0 and the chemotherapeutic agents are administered in therapeutically effective dosages to obtain clinically acceptable 10 results, e.g., reduction or elimination of symptoms or of the tumor. Thus, the compound of formula 1.0 and chemotherapeutic agents can be administered concurrently or consecutively in a treatment protocol. The administration of the chemotherapeutic agents can be made according to treatment protocols already known in the art. 15 In general when more than one chemotherapeutic agent is used in the methods described, and uses of this invention, the chemotherapeutic agents are administered on the same day either concurrently or consecutively in their standard dosage form. For example, the chemotherapeutic agents are usually administered intravenously, preferably by an IV drip using IV solutions well known in the art (e.g., 20 isotonic saline (0.9% NaCI) or dextrose solution (e.g., 5% dextrose)). When two or more chemotherapeutic agents are used, the chemotherapeutic agents are generally administered on the same day; however, those skilled in the art will appreciate that the chemotherapeutic agents can be administered on different days and in different weeks. The skilled clinician can administer the 25 chemotherapeutic agents according to their recommended dosage schedule from the manufacturer of the agent and can adjust the schedule according to the needs of the patient, e.g., based on the patient's response to the treatment. For example, when gemcitabine is used in combination with a platinum coordinator compound, such as, for example, cisplatin, to treat lung cancer, both the gemcitabine and the cisplatin are 30 given on the same day on day one of the treatment cycle, and then gemcitabine is given alone on day 8 and given alone again on day 15 The compounds of this invention and chemotherapeutic agents can be administered in a treatment protocol that usually lasts one to seven weeks, and is repeated typically from 6 to 12 times. Generally the treatment protocol can last one to RECIEVED IPONZ 22 AUGUST 2011 -114- four weeks. Treatment protocols of one to three weeks can also be used. A treatment protocol of one to two weeks can also be used. During this treatment protocol or cycle the compounds of this invention can be administered daily while the chemotherapeutic agents can be administered one or more times a week. Generally, 5 a compound of this invention can be administered daily (i.e., once per day), and in one embodiment twice per day, and the chemotherapeutic agent is administered once a week or once every three weeks. For example, the taxanes (e.g., Paclitaxel (e.g., Taxol®) or Docetaxel (e.g.,Taxotere®)) can be administered once a week or once every three weeks. 10 However, those skilled in the art will appreciate that treatment protocols can be varied according to the needs of the patient. Thus, the combination of compounds (drugs) used in the methods described, and uses of this invention can be administered in variations of the protocols described above. For example, the compounds of this invention can be administered discontinuously rather than 15 continuously during the treatment cycle. Thus, for example, during the treatment cycle the compounds of this invention can be administered daily for a week and then discontinued for a week, with this administration repeating during the treatment cycle. Or the compounds of this invention can be administered daily for two weeks and discontinued for a week, with this administration repeating during the treatment cycle. 20 Thus, the compounds of this invention can be administered daily for one or more weeks during the cycle and discontinued for one or more weeks during the cycle, with this pattern of administration repeating during the treatment cycle. This discontinuous treatment can also be based upon numbers of days rather than a full week. For example, daily dosing for 1 to 6 days, no dosing for 1 to 6 days with this pattern 25 repeating during the treatment protocol. The number of days (or weeks) wherein the compounds of this invention are not dosed do not have to equal the number of days (or weeks) wherein the compounds of this invention are dosed. Usually, if a discontinuous dosing protocol is used, the number of days or weeks that the compounds of this invention are dosed is at least equal or greater than the number of 30 days or weeks that the compounds of this invention are not dosed. The chemotherapeutic agent could be given by bolus or continuous infusion. The chemotherapeutic agent could be given daily to once every week, or once every two weeks, or once every three weeks, or once every four weeks during the treatment cycle. If administered daily during a treatment cycle, this daily dosing can be RECIEVED IPONZ 22 AUGUST 2011 -115- discontinuous over the number of weeks of the treatment cycle. For example, dosed for a week (or a number of days), no dosing for a week (or a number of days, with the pattern repeating during the treatment cycle. The compounds of this invention can be administered orally, preferably as a 5 solid dosage form, and in one embodiment as a capsule, and while the total therapeutically effective daily dose can be administered in one to four, or one to two divided doses per day, generally, the therapeutically effective dose is given once or twice a day, and in one embodiment twice a day. The compounds of this invention can be administered in an amount of about 50 to about 400 mg once per day, and 10 can be administered in an amount of about 50 to about 300 mg once per day. The compounds of this invention are generally administered in an amount of about 50 to about 350 mg twice a day, usually 50 mg to about 200 mg twice a day, and in one embodiment about 75 mg to about 125 mg administered twice a day, and in another embodiment about 100 mg administered twice a day. 15 If the patient is responding, or is stable, after completion of the therapy cycle, the therapy cycle can be repeated according to the judgment of the skilled clinician. Upon completion of the therapy cycles, the patient can be continued on the compounds of this invention at the same dose that was administered in the treatment protocol, or, if the dose was less than 200mg twice a day, the dose can be raised to 20 200 mg twice a day. This maintenance dose can be continued until the patient progresses or can no longer tolerate the dose (in which case the dose can be reduced and the patient can be continued on the reduced dose). The chemotherapeutic agents, used with the compounds of this invention, are administered in their normally prescribed dosages during the treatment cycle (i.e., the 25 chemotherapeutic agents are administered according to the standard of practice for the administration of these drugs). For example: (a) about 30 to about 300 mg/m2 for the taxanes; (b) about 30 to about 100 mg/m2 for Cisplatin; (c) AUC of about 2 to about 8 for Carboplatin; (d) about 2 to about 4 mg/m2 for EGF inhibitors that are antibodies; (e) about 50 to about 500 mg/m2 for EGF inhibitors that are small 30 molecules; (f) about 1 to about 10 mg/m2 for VEGF kinase inhibitors that are antibodies; (g) about 50 to about 2400 mg/m2 for VEGF inhibitors that are small molecules; (h) about 1 to about 20 mg for SERMs; (i) about 500 to about 1250 mg/m2 for the anti-tumor nucleosides 5-Fluorouracil, Gemcitabine and Capecitabine; (j) for the anti-tumor nucleoside Cytarabine (Ara-C) 100-200mg/m2/day for 7 to 10 days RECIEVED IPONZ 22 AUGUST 2011 -116- every 3 to 4 weeks, and high doses for refractory leukemia and lymphoma, i.e., 1 to 3 gm/m2 for one hour every 12 hours for 4-8 doses every 3 to four weeks; (k) for the anti-tumor nucleoside Fludarabine (F-ara-A) 10-25mg/m2/day every 3 to 4 weeks; (I) for the anti-tumor nucleoside Decitabine 30 to 75 mg/m2 for three days every 6 weeks 5 for a maximum of 8 cycles; (m) for the anti-tumor nucleoside Chlorodeoxyadenosine (CdA, 2-CdA) 0.05-0.1 mg/kg/day as continuous infusion for up to 7 days every 3 to 4 weeks; (n) about 1 to about 100 mg/m2 for epothilones; (o) about 1 to about 350 mg/m2 for topoisomerase inhibitors; (p) about 1 to about 50 mg/m2 for vinca alkaloids; (q) for the folate antagonist Methotrexate (MTX) 20-60 mg/m2 by oral, IV or IM every 3 10 to 4 weeks, the intermediate dose regimen is 80-250 mg/m2 IV over 60 minutes every 3 to 4 weeks, and the high dose regimen is 250-1000mg/m2 IV given with leucovorin every 3 to 4 weeks; (r) for the folate antagonist Premetrexed (Alimta) 300-600 mg/m2 (10 minutes IV infusion day 1) every 3 weeks; (s) for the ribonucleotide reductase inhibitor Hydroxyurea (HU) 20-50 mg/kg/day (as needed to bring blood cell counts 15 down); (t) the platinum coordinator compound Oxaliplatin (Eloxatin) 50-100 mg/m2 every 3 to 4 weeks (preferably used for solid tumors such as non-small cell lung cancer, colorectal cancer and ovarian cancer); (u) for the anthracycline daunorubicin 10-50 mg/m2/day IV for 3-5 days every 3 to 4 weeks; (v) for the anthracycline Doxorubicin (Adriamycin) 50-100 mg/m2 IV continuous infusion over 1-4 days every 3 20 to 4 weeks, or 10-40 mg/m2 IV weekly; (w) for the anthracycline Idarubicin 10-30 mg/m2 daily for 1-3 days as a slow IV infusion over 10-20 minutes every 3 to 4 weeks; (x) for the biologic interferon (Intron-A, Roferon) 5 to 20 million III three times per week; (y) for the biologic pegylated interferon (Peg-intron, Pegasys) 3 to 4 micrograms/kg/day chronic sub cutaneous (until relapse or loss of activity); (z) for the 25 biologic Rituximab (Rituxan) (antibody used for non-Hodgkin's lymphoma) 200-400mg/m2 IV weekly over 4-8 weeks for 6 months; (aa) for the alkylating agent temozolomide 75 mg/m2 to 250mg/m2, for example, 150 mg/m2, or for example, 200 mg/m2, such as 200mg/m2 for 5 days; and (bb) for the MEK1 and/or MEK2 inhibitor PD0325901, 15 mg to 30 mg, for example, 15 mg daily for 21 days every 4 weeks. 30 Gleevec can be used orally in an amount of about 200 to about 800 mg/day. Thalidomide (and related imids) can be used orally in amounts of about 200 to about 800 mg/day, and can be contiuously dosed or used until releapse or toxicity. See for example Mitsiades et al., "Apoptotic signaling induced by immunomodulatory thalidomide analogs in human multiple myeloma cells;therapeutic implications", RECIEVED IPONZ 22 AUGUST 2011 -117- Blood, 99(12):4525-30, June 15, 2002, the disclosure of which is incorporated herein by reference thereto. The FPT inhibitor Sarasar® (brand of lonifarnib) can be administered orally (e.g., capsule) in amounts of about 50 to about 200 mg given twice a day, or in 5 amounts of about 75 to about 125 mg given twice a day, or in amounts of about 100 to about 200 mg given twice a day, or in an amount of about 100 mg given twice a day. Paclitaxel (e.g., Taxol®), for example, can be administered once per week in an amount of about 50 to about 100 mg/m2 and in another example about 60 to about 80 10 mg/m2. In another example Paclitaxel (e.g., Taxol®) can be administered once every three weeks in an amount of about 150 to about 250 mg/m2 and in another example about 175 to about 225 mg/m2. In another example, Docetaxel (e.g., Taxotere®) can be administered once per week in an amount of about 10 to about 45 mg/m2. In another example Docetaxel 15 (e.g., Taxotere®) can be administered once every three weeks in an amount of about 50 to about 100 mg/m2. In another example Cisplatin can be administered once per week in an amount of about 20 to about 40 mg/m2. In another example Cisplatin can be administered once every three weeks in an amount of about 60 to about 100 mg/m2. 20 In another example Carboplatin can be administered once per week in an amount to provide an AUC of about 2 to about 3. In another example Carboplatin can be administered once every three weeks in an amount to provide an AUC of about 5 to about 8. Other embodiments of this invention are described below. The embodiments 25 have been numbered for the purpose of making it easier to refer to the embodiments. The term "in any one of Embodiment Nos." or the term "of any of Embodiment Nos.", as used below, means that the particular embodiment using that term is intended to cover any one of the embodiments referred to as if any one of the referred to embodiments had been individually described. "Nos." is an abbreviation for Numbers. 30 Embodiment No. 1 is directed to a compound of formula 1.0, preferably a compound of formula 1.0C, wherein Q is selected from the group consisting of substituents 2.1, 2.2, 2.3, 2.3A, 2.3B, 2.3C, 2.4A, 2.4B, 2.4C, 2.5A, 2.5B, 2.5C, 2.6A, RECIEVED IPONZ 22 AUGUST 2011 -118- 2,1k, 2.7B, 2.7C, 2.8A, 2.8B, 2.8C, 2.9 to 2.14, 2.15, 2.16 (e.g., 2.16A or 2.16B), 2.17, 2.17A, 2.17B, 2.17C, 2.17D, 2.17E, 2.18, 2.19, 2.20, 2.21 and 2.22. Embodiment No. 2 is directed to a compound of formula 1.1 wherein Q is selected from the group consisting of substituents 2.1, 2.2, 2.3, 2.3A, 2.3B, 2.3C, 5 2.4A, 2.4B, 2.4C, 2.5k, 2.5B, 2.5C, 2.6A, 2.1k, 2.7B, 2.7C, 2.8A, 2.8B, 2.8C, 2.9 to 2.14, 2.15, 2.16 (e.g., 2.16A or 2.16B), 2.17, 2.17A, 2.17B, 2.17C, 2.17D, 2.17E, 2.18, 2.19, 2.20, 2.21 and 2.22. Embodiment No. 3 is directed to a compound of formula 1.2 wherein Q is selected from the group consisting of substituents 2.1, 2.2, 2.3, 2.3A, 2.3B, 2.3C, 10 2.4A, 2.4B, 2.4C, 2.5k, 2.5B, 2.5C, 2.6A, 2.1k, 2.7B, 2.7C, 2.8A, 2.8B, 2.8C, 2.9 to 2.14, 2.15, 2.16 (e.g., 2.16A or 2.16B), 2.17, 2.17A, 2.17B, 2.17C, 2.17D, 2.17E, 2.18, 2.19, 2.20, 2.21 and 2.22. Embodiment No. 4 is directed to a compound of formula 1.3 wherein Q is selected from the group consisting of substituents 2.1, 2.2, 2.3, 2.3A, 2.3B, 2.3C, 15 2.4A, 2.4B, 2.4C, 2.5k, 2.5B, 2.5C, 2.6A, 2.1k, 2.7B, 2.7C, 2.8A, 2.8B, 2.8C, 2.9 to 2.14, 2.15, 2.16 (e.g., 2.16A or2.16B), 2.17, 2.17A, 2.17B, 2.17C, 2.17D, 2.17E, 2.18, 2.19, 2.20, 2.21 and 2.22. Embodiment No. 5 is directed to a compound of formula 1.0, preferably a compound of formula 1.0C1 and more preferably a compound of formula 1.0C, (e.g., 20 1.1, 1.1 A, 1.2, 1.2A, 1.3 or 1.3A) wherein substituent Q is 2.1. Embodiment No. 6 is directed to a compound of formula 1.0, preferably a compound of formula 1.0C1 and more preferably a compound of formula 1.0C, (e.g., 1.1, 1.1 A, 1.2, 1.2A, 1.3 or 1.3A) wherein substituent Q is 2.2. Embodiment No. 7 is directed to a compound of formula 1.0 (e.g., 1.1, 1.1 A, 25 1.2, 1.2k, 1.3 or 1.3A) wherein substituent Q is 2.3 (e.g., 2.3A, 2.3B or 2.3C). Embodiment No. 8 is directed to a compound of formula 1.0, preferably a compound of formula 1.0C, (e.g., 1.1, 1.1 A, 1.2, 1.2k, 1.3 or 1,3A) wherein substituent Q is 2.4 (e.g., 2.4A, 2.4B or 2.4C). Embodiment No. 9 is directed to a compound of formula 1.0, preferably a 30 compound of formula 1.0C1 and more preferably a compound of formula 1,0C, (e.g., 1.1, 1.1 A, 1.2, 1.2A, 1.3 or 1.3A) wherein substituent Q is 2.5 (e.g., 2.5k, 2.5B or 2.5C). Embodiment No. 10 is directed to any of compounds of formulas to a compound of formula 1.0, preferably a compound of formula 1.0C1 and more RECIEVED IPONZ 22 AUGUST 2011 -119- preferably a compound of formula 1.0C, (e.g., 1.1, 1.1 A, 1.2, 1.2A, 1.3 or 1,3A) wherein substituent Q is 2.6 (e.g., 2.6A). Embodiment No. 11 is directed to a compound of formula 1.0, preferably a compound of formula 1.0C1 and more preferably a compound of formula 1.0C, (e.g., 5 1.1, 1.1 A, 1.2, 1.2A, 1.3 or 1.3A) wherein substituent Q is 2.7. Embodiment No. 12 is directed to a compound of formula 1.0, preferably a compound of formula 1.0C1 and more preferably a compound of formula 1.0C, (e.g., 1.1, 1.1 A, 1.2, 1.2A, 1.3 or 1,3A) wherein substituent Q is 2.8. Embodiment No. 13 is directed to a compound of formula 1.0, preferably a 10 compound of formula 1.0C1 and more preferably a compound of formula 1.0C, (e.g., 1.1, 1.1 A, 1.2, 1.2A, 1.3 or 1.3A) wherein substituent Q is 2.9. Embodiment No. 14 is directed to a compound of formula 1.0, preferably a compound of formula 1.0C1 and more preferably a compound of formula 1.0C, (e.g., 1.1, 1.1 A, 1.2, 1.2A, 1.3 or 1.3A) wherein substituent Q is 2.10. 15 Embodiment No. 15 is directed to a compound of formula 1.0, preferably a compound of formula 1.0C1 and more preferably a compound of formula 1.0C, (e.g., 1.1, 1.1 A, 1.2, 1.2k, 1.3 or 1.3A) wherein substituent Q is 2.11. Embodiment No. 16 is directed to a compound of formula 1.0, preferably a compound of formula 1.0C1 and more preferably a compound of formula 1.0C, (e.g., 20 1.1, 1.1A, 1.2, 1.2A, 1.3 or 1.3A) wherein substituent Q is 2.12. Embodiment No. 17 is directed to a compound of formula 1.0, preferably a compound of formula 1.0C1 and more preferably a compound of formula 1.0C, (e.g., 1.1, 1.1 A, 1.2, 1.2A, 1.3 or 1.3A) wherein substituent Q is 2.13. Embodiment No. 18 is directed to a compound of formula 1.0, preferably a 25 compound of formula 1.0C1 and more preferably a compound of formula 1.0C, (e.g., 1.1, 1.1 A, 1.2, 1.2A, 1.3 or 1.3A) wherein substituent Q is 2.14. Embodiment No. 19 is directed to a compound of formula 1.0, preferably a compound of formula 1.0C1 and more preferably a compound of formula 1.0C, (e.g., 1.1, 1.1 A, 1.2, 1.2A, 1.3 or 1.3A) wherein substituent Q is 2.15. 30 Embodiment No. 20 is directed to a compound of formula 1.0, preferably a compound of formula 1.0C1 and more preferably a compound of formula 1.0C, (e.g., 1.1, 1.1 A, 1.2, 1.2A, 1.3 or 1.3A) wherein substituent Q is 2.16. Embodiment No. 21 is directed to a compound of formula 1.0, preferably a compound of formula 1.0C1 and more preferably a compound of formula 1.0C, (e.g., RECIEVED IPONZ 22 AUGUST 2011 -120- 1.1, 1.1 A, 1.2, 1.2A, 1.3 or 1.3A) wherein substituent Q is 2.17 (e.g., 2.17A, 2.17B, 2.17C, 2.17D, or 2.17E). Embodiment No. 22 is directed to a compound of formula 1.0, preferably a compound of formula 1.0C1 and more preferably a compound of formula 1.0C, (e.g., 5 1.1, 1.1 A, 1.2, 1.2A, 1.3 or 1.3A) wherein substituent Q is 2.18. Embodiment No. 23 is directed to a compound of formula 1.0, preferably a compound of formula 1.0C1 and more preferably a compound of formula 1.0C, (e.g., 1.1, 1.1A, 1.2, 1.2A, 1.3 or 1.3A) wherein substituent Q is 2.19. Embodiment No. 24 Is directed to a compound of formula 1.0, preferably a 10 compound of formula 1.0C1 and more preferably a compound of formula 1,0C, (e.g., 1.1, 1.1 A, 1.2, 1.2A, 1.3 or 1.3A) wherein substituent Q is 2.20. Embodiment No. 25 is directed to a compound of formula 1.0, preferably a compound of formula 1.0C1 and more preferably a compound of formula 1.0C, (e.g., 1.1, 1,1A, 1.2, 1,2A, 1.3 or 1,3A) wherein substituent Q is 2.21. 15 Embodiment No. 26 is directed to a compound of formula 1.0, preferably a compound of formula 1.0C1 and more preferably a compound of formula 1.0C, (e.g., 1.1, 1.1 A, 1.2, 1,2A, 1.3 or 1.3A) wherein substituent Q is 2.22. Embodiment No. 27 is directed to a compound of formula 1.3 wherein substituent Q is 2.1. 20 Embodiment No. 28 is directed to a compound of formula 1.3 wherein substituent Q is 2.2. Embodiment No. 29 is directed to a compound of formula 1.3 wherein substituent Q is 2.3. Embodiment No. 30 is directed to a compound of formula 1.3 wherein 25 substituent Q is 2.6. Embodiment No. 31 is directed to a compound of formula 1.3 wherein substituent Q is 2.6A. Embodiment No. 32 is directed to a compound of formula 1.3 wherein substituent Q is 2.7A. 30 Embodiment No. 33 is directed to a compound of formula 1.3 wherein substituent Q is 2.7B. Embodiment No. 34 is directed to a compound of formula 1.3 wherein substituent Q is 2.7C. RECIEVED IPONZ 22 AUGUST 2011 -121 - Embodiment No. substituent Q is 2.17. Embodiment No. substituent Q is 2.17A. 5 Embodiment No. substituent Q is 2.17B. Embodiment No. substituent Q is 2.17C. Embodiment No. 10 substituent Q is 2.17D. Embodiment No. 40 is directed to a compound of formula 1.3 wherein substituent Q is 2.17E. Embodiment No. 41 is directed to a compound of formula 1.0, preferably a compound of formula 1.0C1 and more preferably a compound of formula 1.0C, (e.g., 15 1.1, 1.1 A, 1.2,. 1.2A, 1.3 or 1.3A) wherein each R3, R4, R6, and R7 is independently selected from the group consisting of: H and alkyl. Embodiment No. 42 is directed to a compound of formula 1.0, preferably a compound of formula 1.0C1 and more preferably a compound of formula 1.0C, (e.g., 1.1, 1.1 A, 1.2, 1,2A, 1.3 or 1,3A) wherein each R3, R4, R6, and R7 is independently 20 selected from the group consisting of: H and methyl. Embodiment No. 43 is directed to a compound of formula 1.0, preferably a compound of formula 1.0C1 and more preferably a compound of formula 1.0C, (e.g., 1.1, 1,1A, 1.2, 1,2A, 1.3 or 1,3A) wherein each R3, R4, R6, and R7 is H. Embodiment No. 44 is directed to a compound of formula 1.0, preferably a 25 compound of formula 1.0C1 and more preferably a compound of formula 1.0C, (e.g., 1.1, 1.1 A, 1.2, 1.2A, 1.3 or 1.3A) wherein substituent Q is selected from the group consisting of: moieties 2.1, 2.2, 2.3A, 2.3B, and 2.3C. Embodiment No. 45 is directed to a compound of formula 1.0, preferably a compound of formula 1.0C1 and more preferably a compound of formula 1.0C, (e.g., 30 1.1, 1.1 A, 1.2, 1,2A, 1.3 or 1.3A) wherein substituent Q is selected from the group consisting of: moieties 2.1, 2.2, 2.3A, 2.3B, and 2.3C, and each R3, R4, R6, and R7 is independently selected from the group consisting of: H and alkyl. Embodiment No. 46 is directed to a compound of formula 1.0, preferably a compound of formula 1.0C1 and more preferably a compound of formula 1.0C, (e.g., 35 is directed to a compound of formula 1.3 wherein 36 is directed to a compound of formula 1.3 wherein 37 is directed to a compound of formula 1.3 wherein 38 is directed to a compound of formula 1.3 wherein 39 is directed to a compound of formula 1.3 wherein RECIEVED IPONZ 22 AUGUST 2011 -122- 1.1, 1.1 A, 1.2, 1.2A, 1.3 or 1.3A) wherein substituent Q is selected from the group consisting of: moieties 2.1, 2.2, 2.3A, 2.3B, and 2.3C, and each R3, R4, R6, and R7 is independently selected from the group consisting of: H and methyl. Embodiment No. 47 is directed to a compound of formula 1.0, preferably a 5 compound of formula 1.0C1 and more preferably a compound of formula 1,0C, (e.g., 1.1, 1.1 A, 1.2, 1.2A, 1.3 or 1,3A) wherein substituent Q is selected from the group consisting of: moieties 2.1, 2.2, 2.3A, 2.3B, and 2.3C, and each R3, R4, R6, and R7 is H. 10 Embodiment No. 48 is directed to a compound of formula 1.0, preferably a compound of formula 1.0C1 and more preferably a compound of formula 1.0C, (e.g., I.1, 1,1A, 1.2, 1.2A, 1.3 or 1.3A) wherein substituent Q is selected from the group consisting of: moiety 2.17. 15 Embodiment No. 49 is directed to a compound of formula 1.0, preferably a compound of formula 1.0C1 and more preferably a compound of formula 1.0C, (e.g., 1.1, 1.1A, 1.2, 1.2A, 1.3 or 1,3A) wherein substituent Q is selected from the group consisting of: moiety 2.17, and each R3, R4, R6, and R7 is independently selected from the group consisting of: H and alkyl. 20 Embodiment No. 50 is directed to a compound of formula 1.0, preferably a compound of formula 1.0C1 and more preferably a compound of formula 1.0C, (e.g., 1.1, 1.1 A, 1.2, 1.2A, 1.3or1.3A) wherein substituent Q is selected from the group consisting of; moiety 2.17, and each R3, R4, R6, and R7 is independently selected from the group consisting of: H and methyl. 25 Embodiment No. 51 is directed to a compound of formula 1.0, preferably a compound of formula 1.0C1 and more preferably a compound of formula 1.0C, (e.g., 1.1, 1.1 A, 1.2, 1.2A, 1.3 or 1,3A) wherein substituent Q is selected from the group consisting of: moiety 2.17, and each R3, R4, R6, and R7 is H. Embodiment No. 52 is directed to a compound of formula 1.0, preferably a 30 compound of formula 1.0C1 and more preferably a compound of formula 1.0C, (e.g., 1.1, 1.1A, 1.2, 1.2A, 1.3or1.3A) wherein substituent Q is selected from the group consisting of: moieties 2.1, and: (1) each R3, R4, R6, and R7 is independently selected from the group consisting of: H and alkyl, or (2) each R3, R4, R6, and R7 is RECIEVED IPONZ 22 AUGUST 2011 -123- independently selected from the group consisting of: H and methyl, or (3) each R3, R4, R6, and R7 is H. Embodiment No. 53 is directed to a compound of formula 1.0, preferably a compound of formula 1.0C1 and more preferably a compound of formula 1.0C, (e.g., 5 1.1, 1.1 A, 1.2, 1,2A, 1.3 or 1,3A) wherein substituent Q is selected from the group consisting of: moieties 2.2, and: (1) each R3, R4, R6, and R7 is independently selected from the group consisting of: H and alkyl, or (2) each R3, R4, R6, and R7 is independently selected from the group consisting of: H and methyl, or (3) each R3, R4, R6, and R7 is H. 10 Embodiment No. 54 is directed to a compound of formula 1.0, preferably a compound of formula 1.0C1 and more preferably a compound of formula 1.0C, (e.g., 1.1, 1.1 A, 1.2, 1.2A, 1.3 or 1.3A) wherein substituent Q is selected from the group consisting of: moieties 2.3A, 2.3B, 2.3C, and: (1) each R3, R4, R6, and R7 is independently selected from the group consisting of: H and alkyl, or (2) each R3, R4, 15 R6,. and R7 is independently selected from the group consisting of: H and methyl, or (3) each R3, R4, R6, and R7 is H. Embodiment No. 55 is directed to a compound of formula 1.2 or 1.3 wherein each R3, R4, R6, and R7 is independently selected from the group consisting of: H and alkyl. 20 Embodiment No. 56 is directed to a compound of formula 1.2 or 1.3 wherein each R3, R4, R6, and R7 is independently selected from the group consisting of: H and methyl. Embodiment No. 57 is directed to a compound of formula 1.2 or 1.3 wherein each R3, R4, R6, and R7 is H. 25 Embodiment No. 58 is directed to a compound of formula 1.2 or 1.3 wherein substituent Q is selected from the group consisting of: moieties 2.1, 2.2, 2.3A, 2.3B and 2.3C. Embodiment No. 59 is directed to a compound of formula 1.2 or 1.3 wherein substituent Q is selected from the group consisting of: moieties 2.1, 2.2, 2.3A, 2.3B 30 and 2.3C, and each R3, R4, R6, and R7 is independently selected from the group consisting of: H and alkyl. Embodiment No. 60 is directed to a compound of formula 1.2 or 1.3 wherein substituent Q is selected from the group consisting of: moieties 2.1, 2.2, 2.3A, 2.3B RECIEVED IPONZ 22 AUGUST 2011 -124- and 2.3C, and each R3, R4, R6, and R7 is independently selected from the group consisting of: H and methyl. Embodiment No. 61 is directed to a compound of formula 1.2 or 1.3 wherein substituent Q is selected from the group consisting of: moieties 2.1, 2.2, 2.3A, 2.3B 5 and 2.3C, and each R3, R4, R6, and R7 is H. Embodiment No. 62 is directed to a compound of formula 1.2 or 1.3 wherein substituent Q is moiety 2.17. Embodiment No. 63 is directed to a compound of formula 1.2 or 1.3 wherein substituent Q is moiety 2.17, and each R3, R4, R6, and R7 is independently selected 10 from the group consisting of: H and alkyl. Embodiment No. 64 is directed to a compound of formula 1.2 or 1.3 wherein substituent Q is moiety 2.17, and each R3, R4, R6, and R7 is independently selected from the group consisting of: H and methyl. Embodiment No. 65 is directed to a compound of formula 1.2 or 1.3 wherein 15 substituent Q is moiety 2.17, and each R3, R4, R6,.and R7 is H. Embodiment No. 66 is directed to a compound of formula 1.2 or 1.3 wherein substituent Q is selected from the group consisting of: moiety 2.1, and: (1) each R3, R4, R6, and R7 is independently selected from the group consisting of: H and alkyl, or (2) each R3, R4, R6, and R7 is independently selected from the group consisting of: H 20 and methyl, or (3) each R3, R4, R6, and R7 is H. Embodiment No. 67 is directed to a compound of formula 1.2 or 1.3 wherein substituent Q is selected from the group consisting of: moiety 2.2, and: (1) each R3, R4, R6, and R7 is independently selected from the group consisting of: H and alkyl, or (2) each R3, R4, R6, and R7 is independently selected from the group consisting of: H 25 and methyl, or (3) each R3, R4, R6, and R7 is H. Embodiment No. 68 is directed to a compound of formula 1.2 or 1.3 wherein substituent Q is selected from the group consisting of: moieties 2.3A, 2.3B and 2.3C, and: (1) each R3, R4, R6, and R7 is independently selected from the group consisting of: H and alkyl, or (2) each R3, R4, R6, and R7 is independently selected from the 30 group consisting of: H and methyl, or (3) each R3, R4, R6, and R7 is H. Embodiment No. 69 is directed to a compound of formula 1.3 wherein each R3, R4, R6, and R7 is independently selected from the group consisting of: H and alkyl. Embodiment No. 70 is directed to a compound of formula 1.3 wherein each R3, R4, R6, and R7 is independently selected from the group consisting of: H and methyl. RECIEVED IPONZ 22 AUGUST 2011 -125- Embodiment No. 71 is directed to a compound of formula 1.3 wherein each R3, R4, R6, and R7 is H. Embodiment No. 72 is directed to a compound of formula 1.3 wherein substituent Q is selected from the group consisting of: moieties 2.1, 2.2, 2.3A, 2.3B 5 and 2.3C. Embodiment No. 73 is directed to a compound of formula 1.3 wherein substituent Q is selected from the group consisting of: moieties 2.1, 2.2, 2.3A, 2.3B and 2.3C, and each R3, R4, R6, and R7 is independently selected from the group consisting of: H and alkyl. 10 Embodiment No. 74 is directed to a compound of formula 1.3 wherein substituent Q is selected from the group consisting of: moieties 2.1, 2.2, 2.3A, 2.3B and 2.3C, and each R3, R4, R6, and R7 is independently selected from the group consisting of: H and methyl. Embodiment No. 75 is directed to a compound of formula 1.3 wherein 15 substituent Q is selected from the group consisting of: moieties 2.1, 2.2, 2.3A, 2.3B and 2.3C, and each R3, R4, R6, and R7 is H. Embodiment No. 76 is directed to a compound of formula 1.3 wherein substituent Q is moiety 2.17. Embodiment No. 77 is directed to a compound of formula 1.3 wherein 20 substituent Q is moiety 2.17, and each R3, R4, R6, and R7 is independently selected from the group consisting of: H and alkyl. Embodiment No. 78 is directed to a compound of formula 1.3 wherein substituent Q is moiety 2.17, and each R3, R4, R6, and R7 is independently selected from the group consisting of: H and methyl. 25 Embodiment No. 79 is directed to a compound of formula 1.3 wherein substituent Q is moiety 2.17, and each R3, R4, R6, and R7 is H. Embodiment No. 80 is directed to a compound of formula 1.3 wherein substituent Q is selected from the group consisting of: moiety 2.1, and: (1) each R3, R4, R6, and R7 is independently selected from the group consisting of: H and alkyl, or 30 (2) each R3, R4, R6, and R7 is independently selected from the group consisting of: H and methyl, or (3) each R3, R4, R6, and R7 is H. Embodiment No. 81 is directed to a compound of formula 1.3 wherein substituent Q is selected from the group consisting of: moiety 2.2, and: (1) each R3, R4, R6, and R7 is independently selected from the group consisting of: H and alkyl, or RECIEVED IPONZ 22 AUGUST 2011 -126- (2) each R3, R4, R6, and R7 is independently selected from the group consisting of: H and methyl, or (3) each R3, R4, R6, and R7 is H. Embodiment No. 82 is directed to a compound of formula 1.3 wherein substituent Q is selected from the group consisting of: moieties 2.3A1, 2.3B and 2.3C, 5 and: (1) each R3, R4, R6, and R7 is independently selected from the group consisting of: H and alkyl, or (2) each R3, R4, R6, and R7 is independently selected from the group consisting of: H and methyl, or (3) each R3, R4, R6, and R7 is H. Embodiment No. 83 is directed to a compound of formula 1.0, preferably a compound of formula 1.0C1 and more preferably a compound of formula 1.0C, (e.g., 10 1.1, 1.1 A, 1.2, 1.2A, 1.3 or 1.3A) wherein substituent Q is selected from the group consisting of: moieties 2.6, 2.1k, 2.7B and 2.7C. Embodiment No. 84 is directed to a compound of formula 1.0, preferably a compound of formula 1.0C1 and more preferably a compound of formula 1.0C, (e.g., 1.1, 1.1 A, 1.2, 1.2A, 1.3or1.3A) wherein substituent Q is selected from the group 15 consisting of: moieties 2.6, 2.1k, 2.7B and 2.7C, and each R3, R4, R6, and R7 is independently selected from the group consisting of: H and alkyl. Embodiment No. 85 is directed to a compound of formula 1.0, preferably a compound of formula 1.0C1 and more preferably a compound of formula 1.0C, (e.g., 1.1, 1.1 A, 1.2, 1.2k, 1.3 or 1.3A) wherein substituent Q is selected from the group 20 consisting of: moieties 2.6, 2.1k, 2.7B and 2.7C, and each R3, R4, R6, and R7 is independently selected from the group consisting of: H and methyl. Embodiment No. 86 is directed to a compound of formula 1.0, preferably a compound of formula 1.0C1 and more preferably a compound of formula 1.0C, (e.g., 1.1, 1.1 A, 1.2, 1,2k, 1.3 or 1,3A) wherein substituent Q is selected from the group 25 consisting of: moieties 2.6, 2.1k, 2.7B and 2.7C, and each R3, R4, R6, and R7 is H. Embodiment No. 87 is directed to a compound of formula 1.0, preferably a compound of formula 1.0C1 and more preferably a compound of formula 1.0C, (e.g., 1.1, 1.1 A, 1.2, 1.2k, 1.3 or 1,3A) wherein substituent Q is selected from the group consisting of: moiety 2.6, and: (1) each R3, R4, R6, and R7 is independently selected 30 from the group consisting of: H and alkyl, or (2) each R3, R4, R6, and R7 is independently selected from the group consisting of: H and methyl, or (3) each R3, R4, R6, and R7 is H. Embodiment No. 88 is directed to a compound of formula 1.0, preferably a compound of formula 1.0C1 and more preferably a compound of formula 1.0C, (e.g., RECIEVED IPONZ 22 AUGUST 2011 -127- 1.1, 1.1 A, 1.2, 1.2A, 1.3 or 1.3A) wherein substituent Q is selected from the group consisting of: moiety 2.7A, and: (1) each R3, R4, R6, and R7 is independently selected from the group consisting of: H and alkyl, or (2) each R3, R4, R6, and R7 is independently selected from the group consisting of: H and methyl, or (3) each R3, R4, 5 R6, and R7 is H. Embodiment No. 89 is directed to a compound of formula 1.0, preferably a compound of formula 1.0C1 and more preferably a compound of formula 1.0C, (e.g., 1.1, 1.1 A, 1.2, 1.2A, 1.3 or 1,3A) wherein substituent Q is selected from the group consisting of; moieties 2.7B and 2.7C, and: (1) each R3, R4, R6, and R7 is 10 independently selected from the group consisting of: H and alkyl, or (2) each R3, R4, R6, and R7 is independently selected from the group consisting of: H and methyl, or (3) each R3, R4, R6, and R7 is H. Embodiment No. 90 is directed to a compound of formula 1.2 or 1.3 wherein substituent Q is selected from the group consisting of: moieties 2.6, 2.7A, 2.7B and 15 2.7C. Embodiment No. 91 is directed to a compound of formula 1.2 or 1.3 wherein substituent Q is selected from the group consisting of; moieties 2.6, 2.1k, 2.7B and 2.7C, and each R3, R4, R6, and R7 is independently selected from the group consisting of; H and alkyl. 20 Embodiment No. 92 is directed to a compound of formula 1.2 or 1.3 wherein substituent Q is selected from the group consisting of: moieties 2.6, 2.1k, 2.7B and 2.7C, and each R3, R4, R6, and R7 is independently selected from the group consisting of: H and methyl. Embodiment No. 93 is directed to a compound of formula 1.2 or 1.3 wherein 25 substituent Q is selected from the group consisting of: moieties 2.6, 2.1k, 2.7B and 2.7C, and each R3, R4, R6, and R7 is independently selected from the group consisting of: H. Embodiment No. 94 is directed to a compound of formula 1.2 or 1.3 wherein substituent Q is selected from the group consisting of; moiety 2.6, and: (1) each R3, 30 R4, R6, and R7 is independently selected from the group consisting of: H and alkyl, or (2) each R3, R4, R6, and R7 is independently selected from the group consisting of: H and methyl, or (3) each R3, R4, R6, and R7 is H. Embodiment No. 95 is directed to a compound of formula 1.2 or 1.3 wherein substituent Q is selected from the group consisting of: moiety 2.1k, and: (1) each R3, RECIEVED IPONZ 22 AUGUST 2011 -128 - R4, R6, and R7 is independently selected from the group consisting of: H and alkyl, or (2) each R3, R4, R6, and R7 is independently selected from the group consisting of: H and methyl, or (3) each R3, R4, R6, and R7 is H. Embodiment No. 96 is directed to a compound of formula 1.2 or 1.3 wherein 5 substituent Q is selected from the group consisting of: moieties 2.7A and 2.7B, and: (1) each R3, R4, R6, and R7 is independently selected from the group consisting of: H and alkyl, or (2) each R3, R4, R6, and R7 is independently selected from the group consisting of: H and methyl, or (3) each R3, R4, R6, and R7 is H. Embodiment No. 97 is directed to a compound of formula 1.3 wherein 10 substituent Q is selected from the group consisting of: moieties 2.6, 2.1k, 2.7B and 2.7C. Embodiment No. 98 is directed to a compound of formula 1.3 wherein substituent Q is selected from the group consisting of; moieties 2.6, 2.1k, 2.7B and 2.7C, and each R3, R4, R6, and R7 is independently selected from the group consisting 15 of: H and alkyl. Embodiment No. 99 is directed to a compound of formula 1.3 wherein substituent Q is selected from the group consisting of: moieties 2.6, 2.1k, 2.7B and 2.7C, and each R3, R4, R6, and R7 is independently selected from the group consisting of: H and methyl. 20 Embodiment No. 100 is directed to a compound of formula 1.3 wherein substituent Q is selected from the group consisting of: moieties 2.6, 2.1k, 2.7B and 2.7C, and each R3, R4, R6, and R7 is H. Embodiment No. 101 is directed to a compound of formula 1.3 wherein substituent Q is selected from the group consisting of: moiety 2.6, and: (1) each R3, 25 R4, R6, and R7 is independently selected from the group consisting of: H and alkyl, or (2) each R3, R4, R6, and R7 is independently selected from the group consisting of: H and methyl, or (3) each R3, R4, R6, and R7 is H. Embodiment No. 102 is directed to a compound of formula 1.3 wherein substituent Q is selected from the group consisting of: moiety 2.1k, and: (1) each R3, 30 R4, R6, and R7 is independently selected from the group consisting of: H and alkyl, or (2) each R3, R4, R6, and R7 is independently selected from the group consisting of: H and methyl, or (3) each R3, R4, R6, and R7 is H. Embodiment No. 103 is directed to a compound of formula 1.3 wherein substituent Q is selected from the group consisting of: moieties 2.7B and 2.7C, and: RECIEVED IPONZ 22 AUGUST 2011 10 -129- (1) each R3, R4, R6, and R7 is independently selected from the group consisting of: H and alkyl, or (2) each R3, R4, R6, and R7 is independently selected from the group consisting of: H and methyl, or (3) each R3, R4, R6, and R7 is H. Embodiment No. 104 is directed to a compound of any one of Embodiment Nos. 1 to 103, wherein R1 is selected from the group consisting of: h^i>h s h h s -ch2-n—c—<^j ' ch2-n—s(0)2ch3' ch2-n—c—n—ch(ch3)2 ■ s—ch2ch3 o o o s H II 5 H —CH2—N—C—N—C2H5 , ?—CH2-N-C—CH3 h 2 5 ' s || 3 o h -ch2-n—c—ch(ch3)2 1 II o |—c=n _ cf3 i cooh t ch3 , ch2oh , c=c~ch3 , ch2nh2 ( s h s h £ h £ h / \ s h §-n-c—<], >-n-c-c3h7) >-n-c^-ch3 5-n-JJ—A ^_n_c_nh2i 15 o o so so o h h / \ £ h h sh -n—c—n—/> t ? n c n c2h5 , s_n_s_ch3 , O ^ O ^ °2 nh s nh c II H S || ? -c—n—oh , >—c—oh - <—c—0-ch3 , 5 c—nh2 » c~nh-(ch2)2-0-ch3 < S 11 > 11 S 11 s o i y O 20 RECIEVED IPONZ 22 AUGUST 2011 -130- § h2 —c-nh-(ch2)2-oh • s—c—n—c—c—nh2 ! ii s ii h ii O 0 0 ch(ch3)2 h -c—n—ch3 ii O h -c—n—c4h9 ii O -c—n-ch(ch3)2 o H // \ -c-n-ch2-// nn o H // v -c—n—" m ' ii O / .c-k-°H2^A , j_ru_^ o O -c-n—<1 II ^ o HO-^ h i -C—N—CH II O v v HO-. h i -c—n—ch O -O- ^C^°^CH3 h i -c—n—ch II i O 0^ 0^ 9 3 h i -c—n—ch O -c-nh-ch2-ch2-0-ch3 II i > O -c-nh-ch2-ch2-oh, O -c-nh-ch2-c-nh2 II II o o -n 0 \-J , -n ^N' JWV1 HN- n—nh i/WLP hn ^ n J] n—n O , RECIEVED IPONZ 22 AUGUST 2011 -131 yf\s\j\n v/vwr> h3c c=0 / jvw N \=J . n——^ n- hn' ,CH, s' xn X). n^.n och3 och3 . ~N h ,0h c=0 I nh c2h4 n(ch3)2 c=0 I nh I c2h4 nh2 RECIEVED IPONZ 22 AUGUST 2011 -132- 0^ CI chc £ O \ ch, no2 o2n ocr f3c (h3c)2hc och. *OCH3 , och3 r ci RECIEVED IPONZ 22 AUGUST 2011 -133- 0^NhrCH2CH2CH3 hn^c^CH3 ii o °Oc/CH3 vAAA/1 o \—o r^ri "f, f cf3 r^S r^S och, ch3 10 RECIEVED IPONZ 22 AUGUST 2011 -134- O ch3 "ch2ch3 ch3 n och3 ch3 och3 -c2-c^<] h2 i/wvu cf3 N—^ , HsCO"^^^ / II I and N.^-N / h3c Embodiment No. 105 is directed to a compound of any one of Embodiment Nos. 1 to 103, wherein R1 is aryl (e.g., phenyl). RECIEVED IPONZ 22 AUGUST 2011 -135- Embodiment No. 106 is directed to a compound of any one of Embodiment Nos. 1 to 103, wherein R1 is substituted aryl (e.g., substituted phenyl). Embodiment No. 107 is directed to a compound of any one of Embodiment Nos. 1 to 103, wherein R1 is heteroaryl (e.g., pyridyl, such as Embodiment No. 108 is directed to a compound of any one of Embodiment Nos. 1 to 103, wherein R1 is substituted heteroaryl (e.g., substituted pyridyl). Embodiment No. 109 is directed to a compound of any one of Embodiment Nos. 1 to 103, wherein R1 is pyridyl substituted with cycloalkyl (e.g., cyclopropyl). Embodiment No. 110 is directed to a compound of any one of Embodiment Nos. 1 to 103, wherein R1 is pyridyl substituted with cyclopropyl. Embodiment No. 111 is directed to a compound of any one of Embodiment Nos. 1 to 103, wherein R1 is: Embodiment No. 112 is directed to a compound of any one of Embodiment Nos. 1 to 103, wherein R1 is phenyl substituted with halo. Embodiment No. 113 is directed to a compound of any one of Embodiment Nos. 1 to 103, wherein R1 is phenyl substituted with F. Embodiment No. 114 is directed to a compound of any one of Embodiment Nos. 1 to 103, wherein R1 is p-F-phenyl. Embodiment No. 115 is directed to a compound of any one of Embodiment Nos. 1 to 103, wherein R1 is pyridyl substituted with -CF3. Embodiment No. 116 is directed to a compound of any one of Embodiment Nos. 1 to 103, wherein R1 is: Embodiment No. 117 is directed to a compound of any one of Embodiment Nos. 1 to 103, wherein R1 is pyridyl substituted with alkyl. recieved iponz 22 august 2011 -136- Embodiment No. 118 is directed to a compound of any one of Embodiment Nos. 1 to 103, wherein R1 is pyridyl substituted with methyl. Embodiment No. 119 is directed to a compound of any one of Embodiment Nos. 1 to 103, wherein R1 is: Embodiment No. 120 is directed to a compound of any one of Embodiment Nos. 1 to 103 wherein R5 is selected from the group consisting of: 10 n nh2 15 RECIEVED IPONZ 22 AUGUST 2011 -137 A H „N. / n O 'ch-, XH, ^ /ch2ch3 Cr O /°X c ch2ch3 O nv -u Br / N N N n M Br n f , n ch2 -cec k i \\ // -cec h J j h2 -c—c=ch2 h -c—ch3 ii O nch2ch3 RECIEVED IPONZ 22 AUGUST 2011 -138 "cn ch2ch3 Embodiment No. 121 is directed to a compound of any one of Embodiment Nos. 1 to 103 wherein R5 is selected from the group consisting of: nh2 ' ~n' . n nh2 , Embodiment No. 122 is directed to a compound of any one of Embodiment Nos. 1 to 103 wherein R5 is selected from the group consisting of: RECIEVED IPONZ 22 AUGUST 2011 -139- and Embodiment No. 123 is directed to a compound of any one of Embodiment Nos. 1 to 103 wherein R5 is W N Embodiment No. 124 is directed to a compound of any one of Embodiment Nos. 1 to 103 wherein R5 is Embodiment No. 125 is directed to a compound of any one of Embodiment Nos. 1 to 103 wherein R5 is Embodiment No. 126 is directed to a compound of any one of Embodiment Nos. 1 to 103 wherein R5 is Embodiment No. 127 is directed to a compound of any one of Embodiment Nos. 1 to 103 wherein R is /- xx;, n, RECIEVED IPONZ 22 AUGUST 2011 -140- Embodiment No. 128 is directed to a compound of any one of Embodiment Nos. 1 to 103 wherein R1 is selected from the group consisting of the R1 groups of any one of Embodiment Nos. 105, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117 or 118, and wherein R5 is selected from the group consisting of the R5 5 groups in any one of Embodiment Nos. 119, 120, 121, 122, 123, 124, 125 or 126. Embodiment No. 129 is directed to a compound of any one of Embodiment Nos. 1 to 128 wherein R2 is selected from the group consisting of H, -CH2OH and -CH2F. Embodiment No. 130 is directed to a compound of any one of Embodiment 10 Nos. 1 to 128 wherein R2 is H. Embodiment No. 131 is directed to a compound of any one of Embodiment Nos. 1 to 128 wherein R2 is -OR23 wherein R23 is alkyl. Embodiment No. 132 is directed to a compound of any one of Embodiment Nos. 1 to 128 wherein R2 is -OCH3. 15 Embodiment No. 133 is directed to a compound of any one of Embodiment Nos. 1 to 128 wherein R2 is -CN. Embodiment No. 134 is directed to a compound of any one of Embodiment Nos. 1 to 128 wherein R2 is -OCHF2. Embodiment No. 135 is directed to a compound of any one of Embodiment 20 Nos.1 to 30, 32 to 35, 41, 42, 44 to 46, 48 to 50, 52 to 56, 58 to 60, 62 to 64, 66 to 70, 72 to 74, 76 to 78, 80 to 85, 87 to 92, 94 to 99 and 101 to 134 wherein R3 is -CH3, provided that, as those skilled in the art will appreciate, Embodiment No. 135 does not apply to any previous embodiment wherein R3 has already been limited to H. Embodiment No. 136 is directed to a compound of any one of Embodiment 25 Nos.1 to 30, 32 to 35, 41, 42, 44 to 46, 48 to 50, 52 to 56, 58 to 60, 62 to 64, 66 to 70, 72 to 74, 76 to 78, 80 to 85, 87 to 92, 94 to 99 and 101 to 134 wherein R4 is —CH3, provided that, as those skilled in the art will appreciate, Embodiment No. 135 does not apply to any previous embodiment wherein R4 has already been limited to H. Embodiment No. 137 is directed to a compound of any one of Embodiment 30 Nos.1 to 15, 18 to 19, 21 to 30, 32 to 35, 41 to 42, 44 to 46, 48 to 50, 52 to 56, 58 to 60, 62, 64, 66 to 70, 72 to 74, 76 to 78, 80 to 85, 87 to 92, 94 to 99 and 101 to 134 wherein R6 is-CH3, provided that, as those skilled in the art will appreciate, Embodiment No. 135 does not apply to any previous embodiment wherein R6 has RECIEVED IPONZ 22 AUGUST 2011 -141 10 15 20 25 30 already been limited to H, or wherein R6 is absent from the formula (e.g., when Q is 2.12, 2.13 or 2.16). Embodiment No. 138 is directed to a compound of any one of Embodiment Nos.1 to 30, 32 to 35, 41, 42, 44 to 46, 48 to 50, 52 to 56, 58 to 60, 62 to 64, 66 to 70, 72 to 74, 76 to 78, 80 to 85, 87 to 92, 94 to 99 and 101 to 134 wherein R7 is -CH3, provided that, as those skilled in the art will appreciate, Embodiment No. 135 does not apply to any previous embodiment wherein R7 has already been limited to H. Embodiment No. 139 is directed to a compound selected from the group consisting of the final compounds of Examples 1 to 610, and 611. Embodiment No. 140 is directed to a compound selected from the group consisting of the final compounds of Examples 6, 336, 412, 413, 462, 469, 480, 487, 489, and 571. Embodiment No. 141 is directed to a compound selected from the group consisting of the final compounds of Examples 1, 2, 5, 6, 7, 9, 11, 12, 13, 18, 19, 22, 23, 24, 25, 26, 27, 28, 61, 88, 89, 183, 184, 186, 188, 189, 190, 191, 192, 193, 196, 197, 198, 199, 202, 203, 204, 205, 250, 251, 253, 254, 255, 256, 257, 258 and 259. Embodiment No. 142 Embodiment No. 143 Embodiment No. 144 Embodiment No. 145 Embodiment No. 146 Embodiment No. 147 Embodiment No. 148 Embodiment No. 149 Embodiment No. 150 Embodiment No. 151 Embodiment No. 152 Embodiment No. 153 Embodiment No. 154 Embodiment No. 155 Embodiment No. 156 Embodiment No. 157 Embodiment No. 158 Embodiment No. 159 s d s d s d s d s d s d s d s d s d s d s d s d s d s d s d s d s d s d rected to the f rected to the f rected to the f rected to the f rected to the f rected to the f rected to the f rected to the f rected to the f rected to the f rected to the f rected to the f rected to the f rected to the f rected to the f rected to the f rected to the f rected to the f nal compound of Example 6. nal compound of Example 183. nal compound of Example 184. nal compound of Example 186. nal compound of Example 188. nal compound of Example 189. nal compound of Example 190. nal compound of Example 191. nal compound of Example 192. nal compound of Example 193. nal compound of Example 336. nal compound of Example 412. nal compound of Example 413. nal compound of Example 462. nal compound of Example 469. nal compound of Example 480. nal compound of Example 487. nal compound of Example 489. RECIEVED IPONZ 22 AUGUST 2011 -142- Embodiment No. 160 is directed to the final compound of Example 571. Embodiment No. 161 is directed to a compound of any one of Embodiment Nos. 1 to 160 in pure and isolated form. Embodiment No. 162 is directed to a pharmaceutical composition comprising an effective amount of at least one compound (e.g., 1, 2 or 3, or 1 or 2, or 1, and usually 1) of formula 1.0, preferably a compound of formula 1,0C, and a pharmaceutically acceptable carrier. Embodiment No. 163 is directed to a pharmaceutical composition comprising an effective amount of a compound of formula 1.0, preferably a compound of formula 1,0C, and a pharmaceutically acceptable carrier. Embodiment No. 164 is directed to a pharmaceutical composition comprising an effective amount of at least one compound (e.g., 1, 2 or 3, or 1 or 2, or 1, and usually 1) of formula 1.1, and a pharmaceutically acceptable carrier. Embodiment No. 165 is directed to a pharmaceutical composition comprising an effective amount of a compound of formula 1.1 and a pharmaceutically acceptable carrier. Embodiment No. 166 is directed to a pharmaceutical composition comprising an effective amount of at least one compound (e.g., 1, 2 or 3, or 1 or 2, or 1, and usually 1) of formula 1.2, and a pharmaceutically acceptable carrier. Embodiment No. 167 is directed to a pharmaceutical composition comprising an effective amount of a compound of formula 1.2 and a pharmaceutically acceptable carrier. Embodiment No. 168 is directed to a pharmaceutical composition comprising an effective amount of at least one compound (e.g., 1, 2 or 3, or 1 or 2, or 1, and usually 1) of formula 1.3, and a pharmaceutically acceptable carrier. Embodiment No. 169 is directed to a pharmaceutical composition comprising an effective amount of a compound of formula 1.3 and a pharmaceutically acceptable carrier. Embodiment No. 170 is directed to a pharmaceutical composition comprising an effective amount of at least one compound (e.g., 1, 2 or 3, or 1 or 2, or 1, and usually 1) of any one of Embodiment Nos. 1 to 160 and a pharmaceutically acceptable carrier. RECIEVED IPONZ 22 AUGUST 2011 -143- Embodimerit No. 171 is directed to a pharmaceutical composition comprising an effective amount of a compound of any one of Embodiment Nos. 1 to 160 and a pharmaceutically acceptable carrier. Embodiment No. 172 is directed to a pharmaceutical composition comprising 5 an effective amount of at least one compound (e.g., 1, 2 or 3, or 1 or 2, or 1, and usually 1) of Embodiment No. 161 and a pharmaceutically acceptable carrier. Embodiment No. 173 is directed to a pharmaceutical composition comprising an effective amount of one compound of Embodiment No. 161 and a pharmaceutically acceptable carrier. 10 Embodiment No. 174 is directed to a pharmaceutical composition of any one of Embodiment Nos. 162 to 173 further comprising an effective amount of at least one (e.g., 1, 2 or 3, or 1 or 2, or 1, and usually 1) other active pharmaceutically active ingredient. Embodiment No. 175 is directed to a pharmaceutical composition of any one of 15 . Embodiment Nos. 162 to 173 further comprising an effective amount of another (i.e., one other) pharmaceutically active ingredient. Embodiment No. 176 is directed to a pharmaceutical composition of any one of Embodiment Nos. 162 to 173 further comprising an effective amount of at least one (e.g., 1, 2 or 3, or 1 or 2, or 1, and usually 1) chemotherapeutic agent. 20 Embodiment No. 177 is directed to a pharmaceutical composition of any one of Embodiment Nos. 162 to 173 further comprising an effective amount of a chemotherapeutic agent. Embodiment No. 178 described is directed to a method of treating cancer in a patient in need of such treatment, said method comprising administering to said 25 patient an effective amount of at least one (1, 2 or 3, or 1 or 2, or 1, and usually 1) compound of formula 1.0 (preferably formula 1.0C). Embodiment No. 179 described is directed to a method of treating cancer in a patient in need of such treatment, said method comprising administering to said patient an effective amount of one compound of formula 1.0 (preferably formula 30 1.0C). Embodiment No. 180 described is directed to a method of treating cancer in a patient in need of such treatment, said method comprising administering to said patient an effective amount of at least one (1, 2 or 3, or 1 or 2, or 1, and usually 1) compound of formula 1.1. RECIEVED IPONZ 22 AUGUST 2011 -144- Embodiment No. 181 described is directed to a method of treating cancer in a patient in need of such treatment, said method comprising administering to said patient an effective amount of one compound of formula 1.1. Embodiment No. 182 described is directed to a method of treating cancer in a patient in need of such treatment, said method comprising administering to said patient an effective amount of at least one (1, 2 or 3, or 1 or 2, or 1, and usually 1) compound of formula 1.2. Embodiment No. 183 described is directed to a method of treating cancer in a patient in need of such treatment, said method comprising administering to said patient an effective amount of one compound of formula 1.2. Embodiment No. 184 described is directed to a method of treating cancer in a patient in need of such treatment, said method comprising administering to said patient an effective amount of at least one (1, 2 or 3, or 1 or 2, or 1, and usually 1) compound of formula 1.3. Embodiment No. 185 described is directed to a method of treating cancer in a patient in need of such treatment, said method comprising administering to said patient an effective amount of one compound of formula 1.3. Embodiment No. 186 described is directed to a method of treating cancer in a patient in need of such treatment, said method comprising administering to said patient an effective amount of at least one (1, 2 or 3, or 1 or 2, or 1, and usually 1) compound of any one of Embodiment Nos. 1 to 161. Embodiment No. 187 described is directed to a method of treating cancer in a patient in need of such treatment, said method comprising administering to said patient an effective amount of a compound of any one of Embodiment Nos. 1 to 161. Embodiment No. 188 described is directed to a method of treating cancer in any one of Embodiment Nos. 178 to 187 further comprising the administration of an effective amount of at least one (1, 2 or 3, or 1 or 2, or 1, and usually 1) chemotherapeutic agent. Embodiment No. 189 described is directed to a method of treating cancer in any one of Embodiment Nos. 178 to 187 further comprising the administration of an effective amount of a chemotherapeutic agent. Embodiment No. 190 described is directed to a method of treating cancer in a patient in need of such treatment comprising administering to said patient an effective amount of a pharmaceutical composition of any one of Embodiment Nos. 162 to 177. RECIEVED IPONZ 22 AUGUST 2011 -145- Embodiment No. 191 described is directed to a method of treating cancer in a patient in need of such treatment comprising administering to said patient an effective amount of a pharmaceutical composition of any one of Embodiment Nos. 162 to 173. Embodiment No. 192 described is directed to a method of treating cancer in a 5 patient in need of such treatment comprising administering to said patient an effective amount of a pharmaceutical composition of any one of Embodiment Nos. 162 to 173, in combination with an effective amount of at least one (1, 2 or 3, or 1 or 2, or 1, and usually 1) chemotherapeutic agent Embodiment No. 193 described is directed to a method of treating cancer in a 10 patient in need of such treatment comprising administering to said patient an effective amount of a pharmaceutical composition of any one of Embodiment Nos. 162 to 173, in combination with an effective amount of one chemotherapeutic agent. Embodiment No. 194 described is directed to a method of treating cancer of any one of Embodiment Nos. 188, 189, 192 and 193 wherein the chemotherapeutic 15 agent is selected from the group consisting of: paclitaxel, docetaxel, carboplatin, cisplatin, gemcitabine, tamoxifen, Herceptin, Cetuximab, Tarceva, Iressa, bevacizumab, navelbine, IMC-1C11, SU5416 and SU6688. Embodiment No. 195 described is directed to a method of treating cancer of any one of Embodiment Nos. 188, 189, 192 and 193 wherein the chemotherapeutic 20 agent is selected from the group consisting of: paclitaxel, docetaxel, carboplatin, cisplatin, navelbine, gemcitabine, and Herceptin. Embodiment No. 196 described is directed to a method of treating cancer of any one of Embodiment Nos. 188, 189, 192 and 193 wherein the chemotherapeutic agent is selected from the group consisting of: Cyclophasphamide, 5-Fluorouracil, 25 Temozolomide, Vincristine, Cisplatin, Carboplatin, and Gemcitabine. Embodiment No. 197 described is directed to a method of treating cancer of anyone of Embodiment Nos. 188, 189, 192 and 193 wherein the chemotherapeutic agent is selected from the group consisting of: Gemcitabine, Cisplatin and Carboplatin. 30 Also described is a method of treating cancer in a patient in need of such treatment, said treatment comprising administering to said patient a therapeutically effective amount at least one (e.g., 1, 2 or 3, or 1 or 2, or 1, and usually 1) compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 161), and therapeutically effective amounts of at least one (e.g., 1, 2 or 3, or 1 or 2, or 2, or RECIEVED IPONZ 22 AUGUST 2011 -146- 1) chemotherapeutic agent selected from the group consisting of: (1) taxanes, (2) platinum coordinator compounds, (3) epidermal growth factor (EGF) inhibitors that are antibodies, (4) EGF inhibitors that are small molecules, (5) vascular endolithial growth factor (VEGF) inhibitors that are antibodies, (6) VEGF kinase inhibitors that are small 5 molecules, (7) estrogen receptor antagonists or selective estrogen receptor modulators (SERMs), (8) anti-tumor nucleoside derivatives, (9) epothilones, (10) topoisomerase inhibitors, (11) vinca alkaloids, (12) antibodies that are inhibitors of aV(33 integrins, (13) folate antagonists, (14) ribonucleotide reductase inhibitors, (15) anthracyclines, (16) biologies; (17) inhibitors of angiogenesis and/or suppressors of 10 tumor necrosis factor alpha (TNF-alpha) such as thalidomide (or related imid), (18) Bcr/abl kinase inhibitors, (19) MEK1 and/or MEK 2 inhibitors that are small molecules, (20) IGF-1 and IGF-2 inhibitors that are small molecules, (21) small molecule inhibitors of RAF and BRAF kinases, (22) small molecule inhibitors of cell cycle dependent kinases such as CDK1, CDK2, CDK4 and CDK6, (23) alkylating agents, 15 and (24) farnesyl protein transferase inhibitors (also know as FPT inhibitors or FTI (i.e., farnesyl transfer inhibitors)). Also described is a method of treating cancer in a patient in need of such treatment, said treatment comprising administering to said patient a therapeutically effective amount at least one (e.g., 1, 2 or 3, or 1 or 2, or 1, and usually 1) compound 20 of formula 1.0 (for example, as described in anyone of Embodiment Nos. 1 to 161), and therapeutically effective amounts of at least two (e.g., 2 or 3, or 2, and usually 2) different antineoplastic agents selected from the group consisting of: (1) taxanes, (2) platinum coordinator compounds, (3) epidermal growth factor (EGF) inhibitors that are antibodies, (4) EGF inhibitors that are small molecules, (5) vascular endolithial growth 25 factor (VEGF) inhibitors that are antibodies, (6) VEGF kinase inhibitors that are small molecules, (7) estrogen receptor antagonists or selective estrogen receptor modulators (SERMs), (8) anti-tumor nucleoside derivatives, (9) epothilones, (10) topoisomerase inhibitors, (11) vinca alkaloids, (12) antibodies that are inhibitors of aV(33 integrins, (13) folate antagonists, (14) ribonucleotide reductase inhibitors, (15) 30 anthracyclines, (16) biologies; (17) inhibitors of angiogenesis and/or suppressors of tumor necrosis factor alpha (TNF-alpha) such as thalidomide (or related imid), (18) Bcr/abl kinase inhibitors, (19) MEK1 and/or MEK 2 inhibitors that are small molecules, (20) IGF-1 and IGF-2 inhibitors that are small molecules, (21) small molecule inhibitors of RAF and BRAF kinases, (22) small molecule inhibitors of cell cycle RECIEVED IPONZ 22 AUGUST 2011 -147- dependent kinases such as CDK1, CDK2, CDK4 and CDK6, (23) alkylating agents, and (24) farnesyl protein transferase inhibitors (also know as FPT inhibitors or FTI (i.e., farnesyl transfer inhibitors)). Also described is a method of treating cancer in a patient in need of such 5 treatment, said method comprising administering to said patient therapeutically effective amounts at least one (e.g., 1, 2 or 3, or 1 or 2, or 1, and usually 1) compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 161), and an antineoplastic agent selected from the group consisting of: (1) EGF inhibitors that are antibodies, (2) EGF inhibitors that are small molecules, (3) VEGF 10 inhibitors that are antibodies, and (4) VEGF inhibitors that are small molecules. Radiation therapy can also be used in conjunction with this above combination therapy, i.e., the above method using a combination of compounds of the invention and antineoplastic agent can also comprise the administration of a therapeutically effect amount of radiation. 15 Also described is a method of treating leukemias (e.g., acute myeloid leukemia (AML), and chronic myeloid leukemia (CML)) in a patient in need of such treatment, said method comprising administering to said patient therapeutically effective amounts at least one (e.g., 1, 2 or 3, or 1 or 2, or 1, and usually 1) compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 161), 20 and: (1) Gleevec and interferon to treat CML; (2) Gleevec and pegylated interferon to treat CML; (3) Gleevec to treat CML; (4) an anti-tumor nucleoside derivative (e.g., Ara-C) to treat AML; or (5) an anti-tumor nucleoside derivative (e.g., Ara-C) in combination with an anthracycline to treat AML. Also described is a method of treating non-Hodgkin's lymphoma in a patient in 25 need of such treatment, said method comprising administering therapeutically effective amounts at least one (e.g., 1, 2 or 3, or 1 or 2, or 1, and usually 1) compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 161) and: (1) a biologic (e.g., Rituxan); (2) a biologic (e.g., Rituxan) and an antitumor nucleoside derivative (e.g., Fludarabine); or (3) Genasense (antisense to BCL-30 2). Also described is a method of treating multiple myeloma in a patient in need of such treatment, said method comprising administering to said patient therapeutically effective amounts of at least one (e.g., 1, 2 or 3, or 1 or 2, or 1, and usually 1) compound of formula 1.0 (for example, as described in any one of Embodiment Nos. RECIEVED IPONZ 22 AUGUST 2011 -148- 1 to 161) and: (1) a proteosome inhibitor (e.g., PS-341 from Millenium); or (2) Thalidomide (or related imid). Also described is a method of treating cancer in a patient in need of such treatment, said method comprising administering to said patient therapeutically 5 effective amounts of: (a) at least one (e.g., 1, 2 or 3, or 1 or 2, or 1, and usually 1) compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 161), and (b) at least one (e.g., 1, 2 or 3, or 1 or 2, or 2, or 1) antineoplastic agent selected from the group consisting of: (1) taxanes, (2) platinum coordinator compounds, (3) EGF inhibitors that are antibodies, (4) EGF inhibitors that are small 10 molecules, (5) VEGF inhibitors that are antibodies, (6) VEGF kinase inhibitors that are small molecules, (7) estrogen receptor antagonists or selective estrogen receptor modulators, (8) anti-tumor nucleoside derivatives, (9) epothilones, (10) topoisomerase inhibitors, (11) vinca alkaloids, and (12) antibodies that are inhibitors of aVp3 integrins. 15 Also described is a method of treating non small cell lung cancer in a patient in need of such treatment, said method comprising administering to said patient therapeutically effective amounts of: (a) at least one (e.g., 1, 2 or 3, or 1 or 2, or 1, and usually 1) compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 161), and (b) at least one (e.g., 1, 2 or 3, or 1 or 2, or 2, or 1) 20 antineoplastic agent selected from the group consisting of: (1) taxanes, (2) platinum coordinator compounds, (3) EGF inhibitors that are antibodies, (4) EGF inhibitors that are small molecules, (5) VEGF inhibitors that are antibodies, (6) VEGF kinase inhibitors that are small molecules, (7) estrogen receptor antagonists or selective estrogen receptor modulators, (8) anti-tumor nucleoside derivatives, (9) epothilones, 25 (10) topoisomerase inhibitors, (11) vinca alkaloids, and (12) antibodies that are inhibitors of aVp3 integrins. Also described is a method of treating non small cell lung cancer in a patient in need of such treatment, said method comprising administering to said patient therapeutically effective amounts of: (a) at least one (e.g., 1, 2 or 3, or 1 or 2, or 1, 30 and usually 1) compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 161), and (b) at least one (e.g., 1, 2 or 3, or 1 or 2, or 2, or 1) antineoplastic agent selected from the group consisting of: (1) taxanes, (2) platinum coordinator compounds, (3) anti-tumor nucleoside derivatives, (4) topoisomerase inhibitors, and (5) vinca alkaloids. RECIEVED IPONZ 22 AUGUST 2011 -149 - Also described is a method of treating non small cell lung cancer in a patient in need of such treatment, said method comprising administering therapeutically effective amounts of: (a) at least one (e.g., 1, 2 or 3, or 1 or 2, or 1, and usually 1) compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 161), (b) carboplatin, and (c) paclitaxel. Also described is a method of treating non small cell lung cancer in a patient in need of such treatment, said method comprising administering to said patient therapeutically effective amounts of: (a) at least one (e.g., 1, 2 or 3, or 1 or 2, or 1, and usually 1) compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 161), (b) cisplatin, and (c) gemcitabine. Also described is a method of treating non small cell lung cancer in a patient in need of such treatment, said method comprising administering therapeutically effective amounts of: (a) at least one (e.g., 1, 2 or 3, or 1 or 2, or 1, and usually 1) compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 161), (b) carboplatin, and (c) gemcitabine. Also described is a method of treating non small cell lung cancer in a patient in need of such treatment, said method comprising administering therapeutically effective amounts of: (a) at least one (e.g., 1, 2 or 3, or 1 or 2, or 1, and usually 1) compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 161), (b) Carboplatin, and (c) Docetaxel. Also described is a method of treating cancer in a patient in need of such treatment, said method comprising administering therapeutically effective amounts of: (a) at least one (e.g., 1, 2 or 3, or 1 or 2, or 1, and usually 1) compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 161), and (b) an antineoplastic agent selected from the group consisting of: (1) EGF inhibitors that are antibodies, (2) EGF inhibitors that are small molecules, (3) VEGF inhibitors that are antibodies, (4) VEGF kinase inhibitors that are small molecules. Also described is a method of treating squamous cell cancer of the head and neck, in a patient in need of such treatment, said method comprising administering to said patient therapeutically effective amounts of: (a) at least one (e.g., 1, 2 or 3, or 1 or 2, or 1, and usually 1) compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 161), and (b) at least one (e.g., 1, 2 or 3, or 1 or 2, or 2, or 1) antineoplastic agent selected from the group consisting of: (1) taxanes, and (2) platinum coordinator compounds. RECIEVED IPONZ 22 AUGUST 2011 -150- Also described is a method of treating squamous cell cancer of the head and neck, in a patient in need of such treatment, said method comprising administering to said patient therapeutically effective amounts of: (a) at least one (e.g., 1, 2 or 3, or 1 or 2, or 1, and usually 1) compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 161), and (b) at least one (e.g., 1, 2 or 3, or 1 or 2, or 2, or 1) antineoplastic agent selected from the group consisting of: (1) taxanes, (2) platinum coordinator compounds, and (3) anti-tumor nucleoside derivatives (e.g., 5-Fluorouracil). Also described is a method of treating CML in a patient in need of such treatment, said method comprising administering therapeutically effective amounts of: (a) at least one (e.g., 1, 2 or 3, or 1 or 2, or 1, and usually 1) compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 161), (b) Gleevec, and (c) interferon (e.g., Intron-A). Also described is a method of treating CML in a patient in need of such treatment comprising administering therapeutically effective amounts of: (a) at least one (e.g., 1, 2 or 3, or 1 or 2, or 1, and usually 1) compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 161), (b) Gleevec; and (c) pegylated interferon (e.g., Peg-lntron, and Pegasys). Also described is a method of treating CML in a patient in need of such treatment comprising administering therapeutically effective amounts of: (a) at least one (e.g., 1, 2 or 3, or 1 or 2, or 1, and usually 1) compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 161) and (b) Gleevec. Also described is a method of treating CMML in a patient in need of such treatment, said method comprising administering to said patient therapeutically effective amounts of at least one (e.g., 1, 2 or 3, or 1 or 2, or 1, and usually 1) compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 161). Also described is a method of treating AML in a patient in need of such treatment, said method comprising administering to said patient therapeutically effective amounts of: (a) at least one (e.g., 1, 2 or 3, or 1 or 2, or 1, and usually 1) compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 161), and (b) an anti-tumor nucleoside derivative (e.g., Cytarabine (i.e., Ara-C)). Also described is a method of treating AML in a patient in need of such treatment, said method comprising administering to said patient therapeutically RECIEVED IPONZ 22 AUGUST 2011 -151 - effective amounts of: (a) at least one (e.g., 1, 2 or 3, or 1 or 2, or 1, and usually 1) compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 161), (b) an anti-tumor nucleoside derivative (e.g., Cytarabine (i.e., Ara-C)), and (c) an anthracycline. Also described is a method of treating non-Hodgkin's lymphoma in a patient in need of such treatment, said method comprising administering to said patient therapeutically effective amounts of: (a) at least one (e.g., 1, 2 or 3, or 1 or 2, or 1, and usually 1) compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 161), and (b) Rituximab (Rituxan). Also described is a method of treating non-Hodgkin's lymphoma in a patient in need of such treatment, said method comprising administering to said patient therapeutically effective amounts of: (a) at least one (e.g., 1, 2 or 3, or 1 or 2, or 1, and usually 1) compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 161), (b) Rituximab (Rituxan), and (c) an anti-tumor nucleoside derivative (e.g., Fludarabine (i.e., F-ara-A). Also described is a method of treating non-Hodgkin's lymphoma in a patient in need of such treatment, said method comprising administering to said patient therapeutically effective amounts of: (a) at least one (e.g., 1, 2 or 3, or 1 or 2, or 1, and usually 1) compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 161), and (b) Genasense (antisense to BCL-2). Also described is a method of treating multiple myeloma in a patient in need of such treatment, said method comprising administering therapeutically effective amounts of: (a) at least one (e.g., 1, 2 or 3, or 1 or 2, or 1, and usually 1) compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 161), and (b) a proteosome inhibitor (e.g., PS-341 (Millenium)). Also described is a method of treating multiple myeloma in a patient in need of such treatment, said method comprising administering to said patient therapeutically effective amounts of: (a) at least one (e.g., 1, 2 or 3, or 1 or 2, or 1, and usually 1) compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 161), and (b) Thalidomide or related imid. Also described is a method of treating multiple myeloma in a patient in need of such treatment, said method comprising administering therapeutically effective amounts of: (a) at least one (e.g., 1, 2 or 3, or 1 or 2, or 1, and usually 1) compound RECIEVED IPONZ 22 AUGUST 2011 -152- of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 161), and (b) Thalidomide. Also described are methods of treating cancer described herein, particularly those described above, wherein in addition to the administration of the compound of 5 formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 161) and antineoplastic agents, radiation therapy is also administered prior to, during, or after the treatment cycle. Also described is a method for treating cancer (e.g., lung cancer, prostate cancer and myeloid leukemias) in a patient in need of such treatment, said method 10 comprising administering to said patient (1) an effective amount of at least one (e.g., 1, 2 or 3, or 1 or 2, or 1, and usually 1) compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 161), in combination with (2) at least one (e.g., 1, 2 or 3, or 1 or 2, or 2, or 1) antineoplastic agent, microtubule affecting agent and/or radiation therapy. 15 Also described is a method of treating cancer in a patient in need of such treatment, said method comprising administering to said patient an effective amount of at least one (e.g., 1, 2 or 3, or 1 or 2, or 1, and usually 1) compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 161) in combination with an effective amount of at least one (e.g., 1, 2 or 3, or 1 or 2, or 1, and usually 1) 20 signal transduction inhibitor. Thus, in one example (e.g., treating non small cell lung cancer): (1) the compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 161) is administered in an amount of about 50 mg to about 200 mg twice a day, and in another example about 75 mg to about 125 mg administered twice a day, and 25 in yet another example about 100 mg administered twice a day, (2) Paclitaxel (e.g., Taxol® is administered once per week in an amount of about 50 to about 100 mg/m2, and in another example about 60 to about 80 mg/m2, and (3) Carboplatin is administered once per week in an amount to provide an AUC of about 2 to about 3. In another example (e.g., treating non small cell lung cancer): (1) the 30 compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 161) is administered in an amount of about 50 mg to about 200 mg twice a day, and in another example about 75 mg to about 125 mg administered twice a day, and yet in another example about 100 mg administered twice a day, (2) Paclitaxel (e.g., Taxol® is administered once per week in an amount of about 50 to about 100 mg/m2, RECIEVED IPONZ 22 AUGUST 2011 -153- and in another example about 60 to about 80 mg/m2, and (3) Cisplatin is administered once per week in an amount of about 20 to about 40 mg/m2. In another example (e.g., treating non small cell lung cancer): (1) the compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 5 1 to 161) is administered in an amount of about 50 mg to about 200 mg twice a day, and in another example about 75 mg to about 125 mg administered twice a day, and in yet another example about 100 mg administered twice a day, (2) Docetaxel (e.g., Taxotere®) is administered once per week in an amount of about 10 to about 45 mg/m2, and (3) Carboplatin is administered once per week in an amount to provide an 10 AUC of about 2 to about 3. In another example (e.g., treating non small cell lung cancer): (1) the compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 161) is administered in an amount of about 50 mg to about 200 mg twice a day, and in another example about 75 mg to about 125 mg administered twice a day, and 15 in yet another example about 100 mg administered twice a day, (2) Docetaxel (e.g., Taxotere®) is administered once per week in an amount of about 10 to about 45 mg/m2, and (3) Cisplatin is administered once per week in an amount of about 20 to about 40 mg/m2. In another example (e.g., treating non small cell lung cancer): (1) the 20 compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 161) is administered in an amount of about 50 mg to about 200 mg twice a day, and in another example about 75 mg to about 125 mg administered twice a day, and in yet another example about 100 mg administered twice a day, (2) Paclitaxel (e.g., Taxol® is administered once every three weeks in an amount of about 150 to about 25 250 mg/m2, and in another example about 175 to about 225 mg/m2, and in yet another example 175 mg/m2, and (3) Carboplatin is administered once every three weeks in an amount to provide an AUC of about 5 to about 8, and in another example 6. In another example of treating non small cell lung cancer: (1) the compound of 30 formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 161) is administered in an amount of 100 mg administered twice a day, (2) Paclitaxel (e.g., Taxol® is administered once every three weeks in an amount of 175 mg/m2, and (3) RECIEVED IPONZ 22 AUGUST 2011 -154- Carboplatin is administered once every three weeks in an amount to provide an AUC of 6. In another example (e.g., treating non small cell lung cancer): (1) the compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 5 1 to 161) is administered in an amount of about 50 mg to about 200 mg twice a day, and in another example about 75 mg to about 125 mg administered twice a day, and in yet another example about 100 mg administered twice a day, (2) Paclitaxel (e.g., Taxol® is administered once every three weeks in an amount of about 150 to about 250 mg/m2, and in another example about 175 to about 225 mg/m2, and (3) Cisplatin 10 is administered once every three weeks in an amount of about 60 to about 100 mg/m2. In another example (e.g., treating non small cell lung cancer): (1) the compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 161) is administered in an amount of about 50 mg to about 200 mg twice a day, 15 and in another example about 75 mg to about 125 mg administered twice a day, and in yet another example about 100 mg administered twice a day, (2) Docetaxel (e.g., Taxotere® is administered once every three weeks in an amount of about 50 to about 100 mg/m2, and (3) Carboplatin is administered once every three weeks in an amount to provide an AUC of about 5 to about 8. 20 In another example (e.g., treating non small cell lung cancer): (1) the compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 161) is administered in an amount of about 50 mg to about 200 mg twice a day, in another example about 75 mg to about 125 mg administered twice a day, and in yet another example about 100 mg administered twice a day, (2) Docetaxel (e.g., 25 Taxotere® is administered once every three weeks in an amount of about 50 to about 100 mg/m2, and (3) Cisplatin is administered once every three weeks in an amount of about 60 to about 100 mg/m2. In another example for treating non small cell lung cancer using the compounds of formula 1.0, Docetaxel and Carboplatin: (1)the compound of formula 30 1.0 (for example, as described in any one of Embodiment Nos. 1 to 161) is administered in an amount of about 50 mg to about 200 mg twice a day, and in another example about 75 mg to about 125 mg administered twice a day, and in yet another example about 100 mg administered twice a day, (2) Docetaxel (e.g., RECIEVED IPONZ 22 AUGUST 2011 -155- Taxotere® is administered once every three weeks in an amount of about 75 mg/m2, and (3) Carboplatin is administered once every three weeks in an amount to provide an AUC of about 6. In another example of the treatments of non-small cell lung cancer described 5 above the Docetaxel (e.g., Taxotere®) and Cisplatin, the Docetaxel (e.g., Taxotere®) and Carboplatin, the Paclitaxel (e.g., Taxol®) and Carboplatin, or the Paclitaxel (e.g., Taxol®) and Cisplatin are administered on the same day. In another example (e.g., CML): (1)the compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 161) is administered in an amount 10 of about 100 mg to about 200 mg administered twice a day, (2) Gleevec is administered in an amount of about 400 to about 800 mg/day orally, and (3) interferon (Intron-A) is administered in an amount of about 5 to about 20 million IU three times per week. In another example (e.g., CML): (1) the compound of formula 1.0 (for example, 15 as described in any one of Embodiment Nos. 1 to 161) is administered in an amount of about 100 mg to about 200 mg administered twice a day, (2) Gleevec is administered in an amount of about 400 to about 800 mg/day orally, and (3) pegylated interferon (Peg-lntron or Pegasys) is administered in an amount of about 3 to about 6 micrograms/kg/day. 20 In another example (e.g., non-Hodgkin's lymphoma): (1) the compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 161) is administered in an amount of about 50 mg to about 200 mg twice a day, and in another example about 75 mg to about 125 mg administered twice a day, and in yet another example about 100 mg administered twice a day, and (2) Genasense 25 (antisense to BCL-2) is administered as a continuous IV infusion at a dose of about 2 to about 5 mg/kg/day (e.g., 3 mg/kg/day) for 5 to 7 days every 3 to 4 weeks. In another example (e.g., multiple myeloma): (1) the compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 161) is administered in an amount of about 50 mg to about 200 mg twice a day, and in another example 30 about 75 mg to about 125 mg administered twice a day, and in yet another example about 100 mg administered twice a day, and (2) the proteosome inhibitor (e.g., PS-341 - Millenium) is administered in an amount of about 1.5mg/m2 twice weekly for two consecutive weeks with a one week rest period. RECIEVED IPONZ 22 AUGUST 2011 -156- ln another example (e.g., multiple myeloma): (1)the compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 161) is administered in an amount of about 50 mg to about 200 mg twice a day, and in another example about 75 mg to about 125 mg administered twice a day, and in yet another example 5 about 100 mg administered twice a day, and (2) the Thalidomide (or related imid) is administered orally in an amount of about 200 to about 800 mg/day, with dosing being continuous until relapse or toxicity. In one embodiment of the methods of treating cancer described, and uses of this invention, the chemotherapeutic agents are selected from the group consisting of: 10 paclitaxel, docetaxel, carboplatin, cisplatin, gemcitabine, tamoxifen, Herceptin, Cetuximab, Tarceva, Iressa, bevacizumab, navelbine, IMC-1C11, SU5416 and SU6688. In another embodiment of the methods of treating cancer described, and uses of this invention, the chemotherapeutic agents are selected from the group consisting 15 of: paclitaxel, docetaxel, carboplatin, cisplatin, navelbine, gemcitabine, and Herceptin. Thus, one embodiment described is a method of treating cancer comprising administering to a patient in need of such treatment therapeutically effective amounts of the compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 161), a taxane, and a platinum coordination compound. 20 Also described is a method of treating cancer comprising administering to a patient in need of such treatment therapeutically effective amounts of the compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 161), a taxane, and a platinum coordination compound, wherein said compound of formula 1.0 is administered every day, said taxane is administered once per week per cycle, 25 and said platinum coordinator compound is administered once per week per cycle. In another embodiment the treatment is for one to four weeks per cycle. Also described is a method of treating cancer comprising administering to a patient in need of such treatment therapeutically effective amounts of the compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 161), a 30 taxane, and a platinum coordination compound, wherein said compound of formula 1.0 is administered every day, said taxane is administered once every three weeks per cycle, and said platinum coordinator compound is administered once every three weeks per cycle. In another embodiment the treatment is for one to three weeks per cycle. RECIEVED IPONZ 22 AUGUST 2011 -157- Also described is a method of treating cancer comprising administering to a patient in need of such treatment therapeutically effective amounts of the compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 161), paclitaxel, and carboplatin. In another embodiment, said compound of formula 1.0 is 5 administered every day, said paclitaxel is administered once per week per cycle, and said carboplatin is administered once per week per cycle. In another embodiment the treatment is for one to four weeks per cycle. Also described is a method of treating cancer comprising administering to a patient in need of such treatment therapeutically effective amounts of the compound 10 of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 161), paclitaxel, and carboplatin. In another embodiment, said compound of formula 1.0 is administered every day, said paclitaxel is administered once every three weeks per cycle, and said carboplatin is administered once every three weeks per cycle. In another embodiment the treatment is for one to three weeks per cycle. 15 Also described is a. method for treating non small cell lung cancer in a patient in need of such treatment comprising administering daily a therapeutically effective amount of the compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 161), administering a therapeutically effective amount of carboplatin once a week per cycle, and administering a therapeutically effective 20 amount of paclitaxel once a week per cycle, wherein the treatment is given for one to four weeks per cycle. In another embodiment said compound of formula 1.0 is administered twice per day. In another embodiment said carboplatin and said paclitaxel are administered on the same day, and in another embodiment said carboplatin and said paclitaxel are administered consecutively, and in another 25 embodiment said carboplatin is administered after said paclitaxel. Also described is a method for treating non small cell lung cancer in a patient in need of such treatment comprising administering daily a therapeutically effective amount of a compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 161), administering a therapeutically effective amount of 30 carboplatin once every three weeks per cycle, and administering a therapeutically effective amount of paclitaxel once every three weeks per cycle, wherein the treatment is given for one to three weeks. In another embodiment compound of formula 1.0 is administered twice per day. In another embodiment said carboplatin and said paclitaxel are administered on the same day, and in another embodiment RECIEVED IPONZ 22 AUGUST 2011 -158- said carboplatin and said paclitaxel are administered consecutively, and in another embodiment said carboplatin is administered after said paclitaxel. Also described is a method for treating non small cell lung cancer in a patient in need of such treatment comprising administering about 50 to about 200 mg of a 5 compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 161) twice a day, administering carboplatin once per week per cycle in an amount to provide an AUC of about 2 to about 8 (and in another embodiment about 2 to about 3), and administering once per week per cycle about 60 to about 300 mg/m2 (and in another embodiment about 50 to 100mg/m2, and in yet another embodiment about 60 10 to about 80 mg/m2) of paclitaxel, wherein the treatment is given for one to four weeks per cycle. In another embodiment said compound of formula 1.0 is administered in amount of about 75 to about 125 mg twice a day, and in another embodiment about 100 mg twice a day. In another embodiment said carboplatin and said paclitaxel are administered on the same day, and in another embodiment said carboplatin and said 15 paclitaxel are administered consecutively, and in another embodiment said carboplatin is administered after said paclitaxel. Also described is a method for treating non small cell lung cancer in a patient in need of such treatment comprising administering about 50 to about 200 mg of a compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 20 1 to 161) twice a day, administering carboplatin once every three weeks per cycle in an amount to provide an AUC of about 2 to about 8 (in another embodiment about 5 to about 8, and in another embodiment 6), and administering once every three weeks per cycle about 150 to about 250 mg/m2 (and in another embodiment about 175 to about 225 mg/m2, and in another embodiment 175 mg/m2) of paclitaxel, wherein the 25 treatment is given for one to three weeks. In another embodiment said compound of formula 1.0 is administered in an amount of about 75 to about 125 mg twice a day, and in another embodiment about 100 mg twice a day. In another embodiment said carboplatin and said paclitaxel are administered on the same day, and in another embodiment said carboplatin and said paclitaxel are administered consecutively, and 30 in another embodiment said carboplatin is administered after said paclitaxel. Also described are methods of treating cancer as described in the above embodiments (i.e., the embodiments directed to treating cancer and to treating non small cell lung cancer with a taxane and platinum coordinator compound) except that in place of paclitaxel and carboplatin the taxanes and platinum coordinator RECIEVED IPONZ 22 AUGUST 2011 -159- compounds used together in the methods are: (1) docetaxel (Taxotere®) and cisplatin; (2) paclitaxel and cisplatin; and (3) docetaxel and carboplatin. In another embodiment of the methods described, and uses of the invention, cisplatin is used in amounts of about 30 to about 100 mg/m2. In the another embodiment of the methods 5 described, and uses of the invention, docetaxel is used in amounts of about 30 to about 100 mg/m2. Also described is a method of treating cancer comprising administering to a patient in need of such treatment therapeutically effective amounts of a compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 161), a 10 taxane, and an EGF inhibitor that is an antibody. In another embodiment the taxane used is paclitaxel, and the EGF inhibitor is a HER2 antibody (in one embodiment Herceptin) or Cetuximab, and in another embodiment Herceptin is used. The length of treatment, and the amounts and administration of said compound of formula 1.0 and the taxane are as described in the embodiments above. The EGF inhibitor that is 15 an antibody is administered once a week per cycle, and in another embodiment is administered on the same day as the taxane, and in another embodiment is administered consecutively with the taxane. For example, Herceptin is administered in a loading dose of about 3 to about 5 mg/m2 (in another embodiment about 4 mg/m2), and then is administered in a maintenance dose of about 2 mg/m2 once per 20 week per cycle for the remainder of the treatment cycle (usually the cycle is 1 to 4 weeks). In one embodiment the cancer treated is breast cancer. Also described is a method of treating cancer comprising administering to a patient in need of such treatment therapeutically effective amounts of: (1) a compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 25 1 to 161), (2) a taxane, and (3) an antineoplastic agent selected from the group consisting of: (a) an EGF inhibitor that is a small molecule, (b) a VEGF inhibitor that is an antibody, and (c) a VEGF kinase inhibitor that is a small molecule. In another embodiment, the taxane paclitaxel or docetaxel is used. In another embodiment the antineoplastic agent is selected from the group consisting of: tarceva, Iressa, 30 bevacizumab, SU5416, SU6688 and BAY 43-9006. The length of treatment, and the amounts and administration of said compound of formula 1.0 and the taxane are as described in the embodiments above. The VEGF kinase inhibitor that is an antibody is usually given once per week per cycle. The EGF and VEGF inhibitors that are small molecules are usually given daily per cycle. In another embodiment, the VEGF RECIEVED IPONZ 22 AUGUST 2011 -160- inhibitor that is an antibody is given on the same day as the taxane, and in another embodiment is administered concurrently with the taxane. In another embodiment, when the EGF inhibitor that is a small molecule or the VEGF inhibitor that is a small molecule is administered on the same day as the taxane, the administration is concurrently with the taxane. The EGF or VEGF kinase inhibitor is generally administered in an amount of about 10 to about 500 mg/m2. Also described is a method of treating cancer comprising administering to a patient in need of such treatment therapeutically effective amounts of a compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 161), an anti-tumor nucleoside derivative, and a platinum coordination compound. Also described is a method of treating cancer comprising administering to a patient in need of such treatment therapeutically effective amounts of a compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 161), an anti-tumor nucleoside derivative, and a platinum coordination compound, wherein said compound of formula 1.0 is administered every day, said anti-tumor nucleoside derivative is administered once per week per cycle, and said platinum coordinator compound is administered once per week per cycle. Although the treatment can be for one to four weeks per cycle, in one embodiment the treatment is for one to seven weeks per cycle. Also described is a method of treating cancer comprising administering to a patient in need of such treatment therapeutically effective amounts of a compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 161), an anti-tumor nucleoside derivative, and a platinum coordination compound, wherein said compound of formula 1.0 is administered every day, said an anti-tumor nucleoside derivative is administered once per week per cycle, and said platinum coordinator compound is administered once every three weeks per cycle. Although the treatment can be for one to four weeks per cycle, in one embodiment the treatment is for one to seven weeks per cycle. Also described is a method of treating cancer comprising administering to a patient in need of such treatment therapeutically effective amounts of a compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 161), gemcitabine, and cisplatin. In another embodiment, said compound of formula 1.0 is administered every day, said gemcitabine is administered once per week per cycle, RECIEVED IPONZ 22 AUGUST 2011 -161 - and said cisplatin is administered once per week per cycle. In one embodiment the treatment is for one to seven weeks per cycle. Also described is a method of treating cancer comprising administering to a patient in need of such treatment therapeutically effective amounts of a compound of 5 formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 161), gemcitabine, and cisplatin. In another embodiment, said compound of formula 1.0 is administered every day, said gemcitabine is administered once per week per cycle, and said cisplatin is administered once every three weeks per cycle. In another embodiment the treatment is for one to seven weeks. 10 Also described is a method of treating cancer comprising administering to a patient in need of such treatment therapeutically effective amounts of a compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 161), gemcitabine, and carboplatin. In another embodiment said compound of formula 1.0 is administered every day, said gemcitabine is administered once per week per cycle, 15 and. said carboplatin is administered once per week per cycle. In another embodiment the treatment is for one to seven weeks per cycle. Also described is a method of treating cancer comprising administering to a patient in need of such treatment therapeutically effective amounts of a compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 161), 20 gemcitabine, and carboplatin. In another embodiment said compound of formula 1.0 is administered every day, said gemcitabine is administered once per week per cycle, and said carboplatin is administered once every three weeks per cycle. In another embodiment the treatment is for one to seven weeks per cycle. In the above embodiments using gemcitabine, the compound of formula 1.0 25 (for example, as described in any one of Embodiment Nos. 1 to 161) and the platinum coordinator compound are administered as described above for the embodiments using taxanes. Gemcitabine is administered in an amount of about 500 to about 1250 mg/m2. In one embodiment the gemcitabine is administered on the same day as the platinum coordinator compound, and in another embodiment consecutively with the 30 platinum coordinator compound, and in another embodiment the gemcitabine is administered after the platinum coordinator compound. Also described is a method of treating cancer in a patient in need of such treatment comprising administering to said patient a compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 161) and an RECIEVED IPONZ 22 AUGUST 2011 -162- antineoplastic agent selected from: (1) EGF inhibitors that are antibodies, (2) EGF inhibitors that are small molecules, (3) VEGF inhibitors that are antibodies, and (4) VEGF kinase inhibitors that are small molecules all as described above. The treatment is for one to seven weeks per cycle, and generally for one to four weeks per 5 cycle. The compound of formula 1.0 is administered in the same manner as described above for the other embodiments of this invention. The small molecule antineoplastic agents are usually administered daily, and the antibody antineoplastic agents are usually administered once per week per cycle. In one embodiment the antineoplastic agents are selected from the group consisting of: Herceptin, 10 Cetuximab, Tarceva, Iressa, bevacizumab, IMC-1C11, SU5416, SU6688 and BAY 43-9006. In the embodiments wherein a platinum coordinator compound is used as well as at least one other antineoplastic agent, and these drugs are administered consecutively, the platinum coordinator compound is generally administered after the 15 other antineoplastic agents have been administered. Other embodiments include the administration of a therapeutically effective amount of radiation to the patient in addition to the administration of a compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 161) and antineoplastic agents in the embodiments described above. Radiation is 20 administered according to techniques and protocols well know to those skilled in the art. Another embodiment of this invention is directed to a pharmaceutical composition comprising at least two different chemotherapeutic agents and a pharmaceutically acceptable carrier for intravenous administration. Preferably the 25 pharmaceutically acceptable carrier is an isotonic saline solution (0.9% NaCI) or a dextrose solution (e.g., 5% dextrose). Another embodiment of this invention is directed to a pharmaceutical composition comprising a compound of formula 1.0 of the invention (for example, as described in any one of Embodiment Nos. 1 to 161) and at least two different 30 antineoplastic agents and a pharmaceutically acceptable carrier for intravenous administration. Preferably the pharmaceutically acceptable carrier is an isotonic saline solution (0.9% NaCI) or a dextrose solution (e.g., 5% dextrose). Another embodiment of this invention is directed to a pharmaceutical composition comprising a compound of formula 1.0 of the invention (for example, as RECIEVED IPONZ 22 AUGUST 2011 -163- described in any one of Embodiment Nos. 1 to 161) and at least one antineoplastic agent and a pharmaceutically acceptable carrier for intravenous administration. Preferably the pharmaceutically acceptable carrier is an isotonic saline solution (0.9% NaCI) or a dextrose solution (e.g., 5% dextrose). Other embodiments of this invention are directed to the use of a combination of at least one (e.g., one) compound of formula 1.0 of the invention (for example, as described in any one of Embodiment Nos. 1 to 161) and drugs for the treatment of breast cancer, i.e., a combination therapy for the treatment of breast cancer. Those skilled in the art will appreciate that the compounds of formula 1.0 and drugs are generally administered as individual pharmaceutical compositions. The use of a pharmaceutical composition comprising more than one drug is within the scope of this invention. Also described is a method of treating (or preventing) breast cancer (i.e., postmenopausal and premenopausal breast cancer, e.g., hormone-dependent breast cancer) in a patient in need of such treatment comprising administering to said patient a therapeutically effective amount of at least one (e.g., one) compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 161) and a therapeutically effective amount of at least one antihormonal agent selected from the group consisting of: (a) aromatase inhibitors, (b) antiestrogens, and (c) LHRH analogues; and said treatment optionally including the administration of at least one chemotherapeutic agent. The compound of formula 1.0 is preferably administered orally, and in one embodiment is administered in capsule form. Examples of aromatase inhibitors include but are not limited to: Anastrozole (e.g., Arimidex), Letrozole (e.g., Femara), Exemestane (Aromasin), Fadrozole and Formestane (e.g., Lentaron). Examples of antiestrogens include but are not limited to: Tamoxifen (e.g., Nolvadex), Fulvestrant (e.g., Faslodex), Raloxifene (e.g., Evista), and Acolbifene. Examples of LHRH analogues include but are not limited to: Goserelin (e.g., Zoladex) and Leuprolide (e.g., Leuprolide Acetate, such as Lupron or Lupron Depot). Examples of chemotherapeutic agents include but are not limited to: Trastuzumab (e.g., Herceptin), Gefitinib (e.g., Iressa), Erlotinib (e.g., Erlotinib HCI, such as Tarceva), Bevacizumab (e.g., Avastin), Cetuximab (e.g., Erbitux), and Bortezomib (e.g., Velcade). RECIEVED IPONZ 22 AUGUST 2011 -164- Preferably, when more than one antihormonal agent is used, each agent is selected from a different category of agent. For example, one agent is an aromatase inhibitor (e.g., Anastrozole, Letrozole, or Exemestane) and one agent is an antiestrogen (e.g., Tamoxifen or Fulvestrant). Also described is a method of treating or preventing breast cancer in a patient in need of such treatment wherein said treatment comprises administering a therapeutically effective amount of at least one (e.g., one) compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 161) and at least one antihormonal agent selected from the group consisting of: (a) aromatase inhibitors, (b) antiestrogens, and (c) LHRH analogues; and administering an effective amount of at least one chemotherapeutic agent. Also described is a method of treating or preventing breast cancer in a patient in need of such treatment wherein said treatment comprises administering a therapeutically effective amount of at least one (e.g., one) compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 161) and at least one antihormonal agent selected from the group consisting of: (a) aromatase inhibitors, (b) antiestrogens, and (c) LHRH analogues. Also described is a method of treating or preventing breast cancer in a patient in need of such treatment wherein said treatment comprises administering a therapeutically effective amount of at least one (e.g., one) compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 161) and at least one antihormonal agent selected from the group consisting of: (a) aromatase inhibitors, and (b) antiestrogens. Also described is a method of treating or preventing breast cancer in a patient in need of such treatment wherein said treatment comprises administering a therapeutically effective amount of at least one (e.g., one) compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 161), at least one antihormonal agent selected from the group consisting of: (a) aromatase inhibitors and (b) antiestrogens; and at least one chemotherapeutic agent. Also described is a method of treating or preventing breast cancer in a patient in need of such treatment wherein said treatment comprises administering a therapeutically effective amount of at least one (e.g., one) compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 161) and at least one aromatase inhibitor. RECIEVED IPONZ 22 AUGUST 2011 -165- Also described is a method of treating or preventing breast cancer in a patient in need of such treatment wherein said treatment comprises administering a therapeutically effective amount of at least one (e.g., one) compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 161), at least one 5 aromatase inhibitor, and at least one chemotherapeutic agent. Also described is a method of treating or preventing breast cancer in a patient in need of such treatment wherein said treatment comprises administering a therapeutically effective amount of: (1) at least one (e.g., one) compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 161); and (2) at 10 least one antihormonal agent selected from the group consisting of: (a) aromatase inhibitors that are selected from the group consisting of Anastrozole, Letrozole, Exemestane, Fadrozole and Formestane, (b) antiestrogens that are selected from the group consisting of: Tamoxifen, Fulvestrant, Raloxifene, and Acolbifene, and (c) LHRH analogues that are selected from the group consisting of: Goserelin and 15 Leuprolide; and administering an effective amount of at least one chemotherapeutic agent selected from the group consisting of: Trastuzumab, Gefitinib, Erlotinib, Bevacizumab, Cetuximab, and Bortezomib. Also described is a method of treating or preventing breast cancer in a patient in need of such treatment wherein said treatment comprises administering a 20 therapeutically effective amount of: (1) at least one (e.g., one) compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 161); and (2) at least one antihormonal agent selected from the group consisting of: (a) aromatase inhibitors that are selected from the group consisting of Anastrozole, Letrozole, Exemestane, Fadrozole and Formestane, (b) antiestrogens that are selected from the 25 group consisting of: Tamoxifen, Fulvestrant, Raloxifene, and Acolbifene, and (c) LHRH analogues that are selected from the group consisting of: Goserelin and Leuprolide. Also described is a method of treating or preventing breast cancer in a patient in need of such treatment wherein said treatment comprises administering a 30 therapeutically effective amount of: (1) at least one (e.g., one) compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 161); and (2) at least one antihormonal agent selected from the group consisting of: (a) aromatase inhibitors that are selected from the group consisting of Anastrozole, Letrozole, RECIEVED IPONZ 22 AUGUST 2011 -166- Exemestane, Fadrozole and Formestane, and (b) antiestrogens that are selected from the group consisting of: Tamoxifen, Fulvestrant, Raloxifene, and Acolbifene. Also described is a method of treating or preventing breast cancer in a patient in need of such treatment wherein said treatment comprises administering a 5 therapeutically effective amount of: (1) at least one (e.g., one) compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 161); and (2) at least one antihormonal agent selected from the group consisting of: (a) aromatase inhibitors that are selected from the group consisting of Anastrozole, Letrozole, Exemestane, Fadrozole and Formestane, (b) antiestrogens that are selected from the 10 group consisting of: Tamoxifen, Fulvestrant, Raloxifene, and Acolbifene; and administering an effective amount of at least one chemotherapeutic agents are selected from the group consisting of: Trastuzumab, Gefitinib, Erlotinib, Bevacizumab, Cetuximab, and Bortezomib. Also described is a method of treating or preventing breast cancer in a patient 15 in need of such treatment wherein said treatment comprises administering a therapeutically effective amount of: (1) at least one (e.g., one) compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 161); and (2) at least one aromatase inhibitor selected from the group consisting of Anastrozole, Letrozole, Exemestane, Fadrozole and Formestane. 20 Also described is a method of treating or preventing breast cancer in a patient in need of such treatment wherein said treatment comprises administering a therapeutically effective amount of: (1) at least one (e.g., one) compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 161); (2) at least one aromatase inhibitor that is selected from the group consisting of Anastrozole, 25 Letrozole, Exemestane, Fadrozole and Formestane; and (3) administering an effective amount of at least one chemotherapeutic agent selected from the group consisting of: Trastuzumab, Gefitinib, Erlotinib, Bevacizumab, Cetuximab, and Bortezomib. Also described is a method of treating or preventing breast cancer in a patient 30 in need of such treatment wherein said treatment comprises administering a therapeutically effective amount of: (1) at least one (e.g., one) compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 161); (2) at least one aromatase inhibitor; and (3) at least one LHRH analogue. RECIEVED IPONZ 22 AUGUST 2011 -167- Also described is a method of treating or preventing breast cancer in a patient in need of such treatment wherein said treatment comprises administering a therapeutically effective amount of:(1) at least one (e.g., one) compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 161); (2) at least one antiestrogen ; and (3) at least one LHRH analogue. Also described is a method of treating or preventing breast cancer in a patient in need of such treatment wherein said treatment comprises administering a therapeutically effective amount of: (1) at least one (e.g., one) compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 161); (2) at least one aromatase inhibitor that is selected from the group consisting of Anastrozole, Letrozole, Exemestane, Fadrozole and Formestane; and (3) at least one LHRH analogue that is selected from the group consisting of: Goserelin and Leuprolide. Also described is a method of treating or preventing breast cancer in a patient in need of such treatment wherein said treatment comprises administering a therapeutically effective amount of: (1) at least one (e.g., one) compound of.formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 161); (2) at least one antiestrogen that is selected from the group consisting of: Tamoxifen, Fulvestrant, Raloxifene, and Acolbifene; and (3) at least one LHRH analogue that is selected from the group consisting of: Goserelin and Leuprolide. Also described is a method of treating or preventing breast cancer in a patient in need of such treatment wherein said treatment comprises administering a therapeutically effective amount of at least one (e.g., one) compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 161) and Anastrozole. Also described is a method of treating or preventing breast cancer in a patient in need of such treatment wherein said treatment comprises administering a therapeutically effective amount of at least one (e.g., one) compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 161) and Letrazole. Also described is a method of treating or preventing breast cancer in a patient in need of such treatment wherein said treatment comprises administering a therapeutically effective amount of at least one (e.g., one) compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 161) and Exemestane. Also described is a method of treating or preventing breast cancer in a patient in need of such treatment wherein said treatment comprises administering a RECIEVED IPONZ 22 AUGUST 2011 -168- therapeutically effective amount of at least one (e.g., one) compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 161) and and Fadrozole. Also described is a method of treating or preventing breast cancer in a patient 5 in need of such treatment wherein said treatment comprises administering a therapeutically effective amount of at least one (e.g., one) compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 161) and Formestane. Also described is a method of treating or preventing breast cancer in a patient 10 in need of such treatment wherein said treatment comprises administering a therapeutically effective amount of at least one (e.g., one) compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 161) and Tamoxifen. Also described is a method of treating or preventing breast cancer in a patient in need of such treatment wherein said treatment comprises administering a 15 therapeutically effective amount of at least one (e.g., one) compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 161) Fulvestrant. Also described is a method of treating or preventing breast cancer in a patient in need of such treatment wherein said treatment comprises administering a therapeutically effective amount of at least one (e.g., one) compound of formula 1.0 20 (for example, as described in any one of Embodiment Nos. 1 to 161) and Raloxifene. Also described is a method of treating or preventing breast cancer in a patient in need of such treatment wherein said treatment comprises administering a therapeutically effective amount of at least one (e.g., one) compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 161) and Acolbifene. 25 Also described is a method of treating or preventing breast cancer in a patient in need of such treatment wherein said treatment comprises administering a therapeutically effective amount of at least one (e.g., one) compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 161) and Goserelin. Also described is a method of treating or preventing breast cancer in a patient 30 in need of such treatment wherein said treatment comprises administering a therapeutically effective amount of at least one (e.g., one) compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 161) and and Leuprolide. RECIEVED IPONZ 22 AUGUST 2011 -169- Also described is a method of treating or preventing breast cancer in a patient in need of such treatment wherein said treatment comprises administering a therapeutically effective amount of at least one (e.g., one) compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 161), Anastrozole, and an antiestrogen selected from the group consisting of: Tamoxifen, Fulvestrant, Raloxifene, and Acolbifene. Also described is a method of treating or preventing breast cancer in a patient in need of such treatment wherein said treatment comprises administering a therapeutically effective amount of at least one (e.g., one) compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 161), Letrozole, and an antiestrogen selected from the group consisting of: Tamoxifen, Fulvestrant, Raloxifene, and Acolbifene. Also described is a method of treating or preventing breast cancer in a patient in need of such treatment wherein said treatment comprises administering a therapeutically effective amount of at least one (e.g., one) compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 161), Exemestane, and an antiestrogen selected from the group consisting of: Tamoxifen, Fulvestrant, Raloxifene, and Acolbifene. Also described is a method of treating or preventing breast cancer in a patient in need of such treatment wherein said treatment comprises administering a therapeutically effective amount of at least one (e.g., one) compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 161), Fadrozole, and an antiestrogen selected from the group consisting of: Tamoxifen, Fulvestrant, Raloxifene, and Acolbifene. Also described is a method of treating or preventing breast cancer in a patient in need of such treatment wherein said treatment comprises administering a therapeutically effective amount of at least one (e.g., one) compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 161), Formestane, and an antiestrogen selected from the group consisting of: Tamoxifen, Fulvestrant, Raloxifene, and Acolbifene. Also described is a method of treating or preventing breast cancer in a patient in need of such treatment wherein said treatment comprises administering a therapeutically effective amount of at least one (e.g., one) compound of formula 1.0 RECIEVED IPONZ 22 AUGUST 2011 -170- (for example, as described in any one of Embodiment Nos. 1 to 161), Anastrozole, and Tamoxifen. Also described is a method of treating or preventing breast cancer in a patient in need of such treatment wherein said treatment comprises administering a therapeutically effective amount of at least one (e.g., one) compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 161), Letrozole, and Tamoxifen. Also described is a method of treating or preventing breast cancer in a patient in need of such treatment wherein said treatment comprises administering a therapeutically effective amount of at least one (e.g., one) compound of formula 1.0 (for example, as described in anyone of Embodiment Nos. 1 to 161), Exemestane, and Tamoxifen. Also described is a method of treating or preventing breast cancer in a patient in need of such treatment wherein said treatment comprises administering a therapeutically effective amount of at least one (e.g., one) compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 161), Fadrozole, and Tamoxifen. Also described is a method of treating or preventing breast cancer in a patient in need of such treatment wherein said treatment comprises administering a therapeutically effective amount of at least one (e.g., one) compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 161), Formestane, and Tamoxifen. Also described is a method of treating or preventing breast cancer in a patient in need of such treatment wherein said treatment comprises administering a therapeutically effective amount of at least one (e.g., one) compound of formula 1.0 (for example, as described in anyone of Embodiment Nos. 1 to 161), Anastrozole, and Fulvestrant. Also described is a method of treating or preventing breast cancer in a patient in need of such treatment wherein said treatment comprises administering a therapeutically effective amount of at least one (e.g., one) compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 161), Letrozole, and Fulvestrant. Also described is a method of treating or preventing breast cancer in a patient in need of such treatment wherein said treatment comprises administering a RECIEVED IPONZ 22 AUGUST 2011 -171 - therapeutically effective amount of at least one (e.g., one) compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 161), Exemestane, and Fulvestrant. Also described is a method of treating or preventing breast cancer in a patient in need of such treatment wherein said treatment comprises administering a therapeutically effective amount of at least one (e.g., one) compound of formula 1.0 (for example, as described in anyone of Embodiment Nos. 1 to 161), Fadrozole, and Fulvestrant. Also described is a method of treating or preventing breast cancer in a patient in need of such treatment wherein said treatment comprises administering a therapeutically effective amount of at least one (e.g., one) compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 161), Formestane, and Fulvestrant. Also described is a method of treating or preventing breast cancer in a patient in need of such treatment wherein said treatment comprises administering a therapeutically effective amount of at least one (e.g., one) compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 161), Anastrozole, and a chemotherapeutic agent selected from the group consisting of: Trastuzumab, Gefitinib, Erlotinib, Bevacizumab, Cetuximab, and Bortezomib. Also described is a method of treating or preventing breast cancer in a patient in need of such treatment wherein said treatment comprises administering a therapeutically effective amount of at least one (e.g., one) compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 161), Letrozole, and a chemotherapeutic agent selected from the group consisting of: Trastuzumab, Gefitinib, Erlotinib, Bevacizumab, Cetuximab, and Bortezomib. Also described is a method of treating or preventing breast cancer in a patient in need of such treatment wherein said treatment comprises administering a therapeutically effective amount of at least one (e.g., one) compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 161), Exemestane, and a chemotherapeutic agent selected from the group consisting of: Trastuzumab, Gefitinib, Erlotinib, Bevacizumab, Cetuximab, and Bortezomib. Also described is a method of treating or preventing breast cancer in a patient in need of such treatment wherein said treatment comprises administering a therapeutically effective amount of at least one (e.g., one) compound of formula 1.0 RECIEVED IPONZ 22 AUGUST 2011 -172- (for example, as described in any one of Embodiment Nos. 1 to 161), Fadrozole, and a chemotherapeutic agent selected from the group consisting of: Trastuzumab, Gefitinib, Erlotinib, Bevacizumab, Cetuximab, and Bortezomib. Also described is a method of treating or preventing breast cancer in a patient in need of such treatment wherein said treatment comprises administering a therapeutically effective amount of at least one (e.g., one) compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 161), Formestane, and a chemotherapeutic agent selected from the group consisting of: Trastuzumab, Gefitinib, Erlotinib, Bevacizumab, Cetuximab, and Bortezomib. Also described is a method of treating or preventing breast cancer in a patient in need of such treatment wherein said treatment comprises administering a therapeutically effective amount of at least one (e.g., one) compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 161), Tamoxifen, and a chemotherapeutic agent selected from the group consisting of: Trastuzumab, Gefitinib, Erlotinib, Bevacizumab, Cetuximab, and Bortezomib. Also described is a method of treating or preventing breast cancer in a patient in need of such treatment wherein said treatment comprises administering a therapeutically effective amount of at least one (e.g., one) compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 161), Fulvestrant, and a chemotherapeutic agent selected from the group consisting of: Trastuzumab, Gefitinib, Erlotinib, Bevacizumab, Cetuximab, and Bortezomib. Also described is a method of treating or preventing breast cancer in a patient in need of such treatment wherein said treatment comprises administering a therapeutically effective amount of at least one (e.g., one) compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 161), Raloxifene, and a chemotherapeutic agent selected from the group consisting of: Trastuzumab, Gefitinib, Erlotinib, Bevacizumab, Cetuximab, and Bortezomib. Also described is a method of treating or preventing breast cancer in a patient in need of such treatment wherein said treatment comprises administering a therapeutically effective amount of at least one (e.g., one) compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 161), Acolbifene, and a chemotherapeutic agent selected from the group consisting of: Trastuzumab, Gefitinib, Erlotinib, Bevacizumab, Cetuximab, and Bortezomib. RECIEVED IPONZ 22 AUGUST 2011 -173- Also described is a method of treating or preventing breast cancer in a patient in need of such treatment wherein said treatment comprises administering a therapeutically effective amount of at least one (e.g., one) compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 161), Goserelin, and 5 a chemotherapeutic agent selected from the group consisting of: Trastuzumab, Gefitinib, Erlotinib, Bevacizumab, Cetuximab, and Bortezomib. Also described is a method of treating or preventing breast cancer in a patient in need of such treatment wherein said treatment comprises administering a therapeutically effective amount of at least one (e.g., one) compound of formula 1.0 10 (for example, as described in any one of Embodiment Nos. 1 to 161), Leuprolein, and a chemotherapeutic agent selected from the group consisting of: Trastuzumab, Gefitinib, Erlotinib, Bevacizumab, Cetuximab, and Bortezomib. Also described is a method of treating or preventing breast cancer in a patient in need of such treatment wherein said treatment comprises administering a 15 therapeutically effective amount of at least one (e.g., one) compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 161), Anastrozole, an antiestrogen selected from the group consisting of: Tamoxifen, Fulvestrant, Raloxifene, and Acolbifene, and a chemotherapeutic agent selected from the group consisting of: Trastuzumab, Gefitinib, Erlotinib, Bevacizumab, Cetuximab, and 20 Bortezomib. Also described is a method of treating or preventing breast cancer in a patient in need of such treatment wherein said treatment comprises administering a therapeutically effective amount of at least one (e.g., one) compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 161), Letrozole, an 25 antiestrogen selected from the group consisting of: Tamoxifen, Fulvestrant, Raloxifene, and Acolbifene, and a chemotherapeutic agent selected from the group consisting of: Trastuzumab, Gefitinib, Erlotinib, Bevacizumab, Cetuximab, and Bortezomib. Also described is a method of treating or preventing breast cancer in a patient 30 in need of such treatment wherein said treatment comprises administering a therapeutically effective amount of at least one (e.g., one) compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 161), Exemestane, an antiestrogen selected from the group consisting of: Tamoxifen, Fulvestrant, Raloxifene, and Acolbifene, and a chemotherapeutic agent selected from the group RECIEVED IPONZ 22 AUGUST 2011 -174- consisting of: Trastuzumab, Gefitinib, Erlotinib, Bevacizumab, Cetuximab, and Bortezomib. Also described is a method of treating or preventing breast cancer in a patient in need of such treatment wherein said treatment comprises administering a 5 therapeutically effective amount of at least one (e.g., one) compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 161), Fadrozole, an antiestrogen selected from the group consisting of: Tamoxifen, Fulvestrant, Raloxifene, and Acolbifene, and a chemotherapeutic agent selected from the group consisting of: Trastuzumab, Gefitinib, Erlotinib, Bevacizumab, Cetuximab, and 10 Bortezomib. Also described is a method of treating or preventing breast cancer in a patient in need of such treatment wherein said treatment comprises administering a therapeutically effective amount of at least one (e.g., one) compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 161), Formestane, an 15 antiestrogen selected from the group consisting of: Tamoxifen, Fulvestrant, Raloxifene, and Acolbifene, and a chemotherapeutic agent selected from the group consisting of: Trastuzumab, Gefitinib, Erlotinib, Bevacizumab, Cetuximab, and Bortezomib. Also described is a method of treating or preventing breast cancer in a patient 20 in need of such treatment wherein said treatment comprises administering a therapeutically effective amount of at least one (e.g., one) compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 161), Anastrozole, Tamoxifen, and a chemotherapeutic agent selected from the group consisting of: Trastuzumab, Gefitinib, Erlotinib, Bevacizumab, Cetuximab, and Bortezomib. 25 Also described is a method of treating or preventing breast cancer in a patient in need of such treatment wherein said treatment comprises administering a therapeutically effective amount of at least one (e.g., one) compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 161), Letrozole, Tamoxifen, and a chemotherapeutic agent selected from the group consisting of: 30 Trastuzumab, Gefitinib, Erlotinib, Bevacizumab, Cetuximab, and Bortezomib. Also described is a method of treating or preventing breast cancer in a patient in need of such treatment wherein said treatment comprises administering a therapeutically effective amount of at least one (e.g., one) compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 161), Exemestane, RECIEVED IPONZ 22 AUGUST 2011 -175- Tamoxifen, and a chemotherapeutic agent selected from the group consisting of: Trastuzumab, Gefitinib, Erlotinib, Bevacizumab, Cetuximab, and Bortezomib. Also described is a method of treating or preventing breast cancer in a patient in need of such treatment wherein said treatment comprises administering a therapeutically effective amount of at least one (e.g., one) compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 161), Fadrozole, Tamoxifen, and a chemotherapeutic agent selected from the group consisting of: Trastuzumab, Gefitinib, Erlotinib, Bevacizumab, Cetuximab, and Bortezomib. Also described is a method of treating or preventing breast cancer in a patient in need of such treatment wherein said treatment comprises administering a therapeutically effective amount of at least one (e.g., one) compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 161), Formestane, Tamoxifen, and a chemotherapeutic agent selected from the group consisting of: Trastuzumab, Gefitinib, Erlotinib, Bevacizumab, Cetuximab, and Bortezomib. Also described is a method of treating or preventing breast cancer in a patient in need of such treatment wherein said treatment comprises administering a therapeutically effective amount of at least one (e.g., one) compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 161), Anastrozole, Fulvestrant, and a chemotherapeutic agent selected from the group consisting of: Trastuzumab, Gefitinib, Erlotinib, Bevacizumab, Cetuximab, and Bortezomib. Also described is a method of treating or preventing breast cancer in a patient in need of such treatment wherein said treatment comprises administering a therapeutically effective amount of at least one (e.g., one) compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 161), Letrozole, Fulvestrant, and a chemotherapeutic agent selected from the group consisting of: Trastuzumab, Gefitinib, Erlotinib, Bevacizumab, Cetuximab, and Bortezomib. Also described is a method of treating or preventing breast cancer in a patient in need of such treatment wherein said treatment comprises administering a therapeutically effective amount of at least one (e.g., one) compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 161), Exemestane, Fulvestrant, and a chemotherapeutic agent selected from the group consisting of: Trastuzumab, Gefitinib, Erlotinib, Bevacizumab, Cetuximab, and Bortezomib. Also described is a method of treating or preventing breast cancer in a patient in need of such treatment wherein said treatment comprises administering a RECIEVED IPONZ 22 AUGUST 2011 -176- therapeutically effective amount of at least one (e.g., one) compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 161), Fadrozole, Fulvestrant, and a chemotherapeutic agent selected from the group consisting of: Trastuzumab, Gefitinib, Erlotinib, Bevacizumab, Cetuximab, and Bortezomib. Also described is a method of treating or preventing breast cancer in a patient in need of such treatment wherein said treatment comprises administering a therapeutically effective amount of at least one (e.g., one) compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 161), Formestane, Fulvestrant, and a chemotherapeutic agent selected from the group consisting of: Trastuzumab, Gefitinib, Erlotinib, Bevacizumab, Cetuximab, and Bortezomib. Also described is a method of treating or preventing breast cancer in a patient in need of such treatment wherein said treatment comprises administering a therapeutically effective amount of at least one (e.g., one) compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 161), Goserelin and Tamoxifen. Also described is a method of treating or preventing breast cancer in a patient in need of such treatment wherein said treatment comprises administering a therapeutically effective amount of at least one (e.g., one) compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 161), Goserelin, and Fulvestrant. Also described is a method of treating or preventing breast cancer in a patient in need of such treatment wherein said treatment comprises administering a therapeutically effective amount of at least one (e.g., one) compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 161), Goserelin, and Raloxifene. Also described is a method of treating or preventing breast cancer in a patient in need of such treatment wherein said treatment comprises administering a therapeutically effective amount of at least one (e.g., one) compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 161), Goserelin and Acolbifene. Also described is a method of treating or preventing breast cancer in a patient in need of such treatment wherein said treatment comprises administering a therapeutically effective amount of at least one (e.g., one) compound of formula 1.0 RECIEVED IPONZ 22 AUGUST 2011 -177- (for example, as described in any one of Embodiment Nos. 1 to 161), Leuprolide, and Tamoxifen. Also described is a method of treating or preventing breast cancer in a patient in need of such treatment wherein said treatment comprises administering a therapeutically effective amount of at least one (e.g., one) compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 161), Leuprolide, and Fulvestrant. Also described is a method of treating or preventing breast cancer in a patient in need of such treatment wherein said treatment comprises administering a therapeutically effective amount of at least one (e.g., one) compound of formula 1.0 (for example, as described in anyone of Embodiment Nos. 1 to 161), Leuprolide, and Raloxifene. Also described is a method of treating or preventing breast cancer in a patient in need of such treatment wherein said treatment comprises administering a therapeutically effective amount of at least one (e.g., one) compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 161), Leuprolide and Acolbifene. Also described is a method of treating or preventing breast cancer in a patient in need of such treatment wherein said treatment comprises administering a therapeutically effective amount of at least one (e.g., one) compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 161), Goserelin and Anastrozole. Also described is a method of treating or preventing breast cancer in a patient in need of such treatment wherein said treatment comprises administering a therapeutically effective amount of at least one (e.g., one) compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 161), Goserelin and Letrozole. Also described is a method of treating or preventing breast cancer in a patient in need of such treatment wherein said treatment comprises administering a therapeutically effective amount of at least one (e.g., one) compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 161), Goserelin and Exemestane. Also described is a method of treating or preventing breast cancer in a patient in need of such treatment wherein said treatment comprises administering a RECIEVED IPONZ 22 AUGUST 2011 -178- therapeutically effective amount of at least one (e.g., one) compound of formula 1.0 (for example, as described in anyone of Embodiment Nos. 1 to 161), Goserelin and Fadrozole. Also described is a method of treating or preventing breast cancer in a patient in need of such treatment wherein said treatment comprises administering a therapeutically effective amount of at least one (e.g., one) compound of formula 1.0 (for example, as described in anyone of Embodiment Nos. 1 to 161), Goserelin and Formestane. Also described is a method of treating or preventing breast cancer in a patient in need of such treatment wherein said treatment comprises administering a therapeutically effective amount of at least one (e.g., one) compound of formula 1.0 (for example, as described in anyone of Embodiment Nos. 1 to 161), Leuprolide and Anastrozole. Also described is a method of treating or preventing breast cancer in a patient in need of such treatment wherein said treatment comprises administering a therapeutically effective amount of at least one (e.g., one) compound of formula 1.0 (for example, as described in anyone of Embodiment Nos. 1 to 161), Leuprolide and Letrozole. Also described is a method of treating or preventing breast cancer in a patient in need of such treatment wherein said treatment comprises administering a therapeutically effective amount of at least one (e.g., one) compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 161), Leuprolide and Exemestane. Also described is a method of treating or preventing breast cancer in a patient in need of such treatment wherein said treatment comprises administering a therapeutically effective amount of at least one (e.g., one) compound of formula 1.0 (for example, as described in anyone of Embodiment Nos. 1 to 161), Leuprolide and Fadrozole. Also described is a method of treating or preventing breast cancer in a patient in need of such treatment wherein said treatment comprises administering a therapeutically effective amount of at least one (e.g., one) compound of formula 1.0 (for example, as described in anyone of Embodiment Nos. 1 to 161), Leuprolide and Formestane. RECIEVED IPONZ 22 AUGUST 2011 -179- Also described is the treatment or prevention of breast cancer in a patient in need of such treatment, said treatment comprising the administration of a therapeutically effective amount of at least one (e.g., one) compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 161) and Anastrozole. Also described is the treatment or prevention of breast cancer in a patient in need of such treatment, said treatment comprising the administration of a therapeutically effective amount of at least one (e.g., one) compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 161) and Letrozole. Also described is the treatment or prevention of breast cancer in a patient in need of such treatment, said treatment comprising the administration of a therapeutically effective amount of at least one (e.g., one) compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 161) and Exemestane. Also described is the treatment or prevention of breast cancer in a patient in need of such treatment, said treatment comprising the administration of a therapeutically effective amount of at least one (e.g., one) compound of formula 1.0 (for example, as described in anyone of Embodiment Nos. 1 to 161) and Tamoxifen. Also described is the treatment or prevention of breast cancer in a patient in need of such treatment, said treatment comprising the administration of a therapeutically effective amount of at least one (e.g., one) compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 161) and Fulvestrant. Also described is the treatment or prevention of breast cancer in a patient in need of such treatment, said treatment comprising the administration of a therapeutically effective amount of at least one (e.g., one) compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 161), Anastrozole, and Fulvestrant. Also described is the treatment or prevention of breast cancer in a patient in need of such treatment, said treatment comprising the administration of a therapeutically effective amount of at least one compound of formula I (e.g., one), Letrozole, and Fulvestrant. Also described is the treatment or prevention of breast cancer in a patient in need of such treatment, said treatment comprising the administration of a therapeutically effective amount of at least one (e.g., one) compound of formula 1.0 RECIEVED IPONZ 22 AUGUST 2011 -180- (for example, as described in anyone of Embodiment Nos. 1 to 161), Exemestane, and Fulvestrant. Also described is the treatment or prevention of breast cancer in a patient in need of such treatment, said treatment comprising the administration of a therapeutically effective amount of at least one (e.g., one) compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 161), Anastrozole, and Tamoxifen. Also described is the treatment or prevention of breast cancer in a patient in need of such treatment, said treatment comprising the administration of a therapeutically effective amount of at least one (e.g., one) compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 161), Letrozole, and Tamoxifen. Also described is the treatment or prevention of breast cancer in a patient in need of such treatment, said treatment comprising the administration of a therapeutically effective amount of at least one (e.g., one) compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 161), Exemestane, and Tamoxifen. Other embodiments are directed to any of the above described embodiments for the treatment of Breast Cancer wherein the chemotherapeutic agent is Trastuzumab. Other embodiments are directed to any of the above described embodiments for the treatment or prevention of Breast Cancer wherein the method is directed to the treatment of breast cancer. The compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 161), antihormonal agents and chemotherapeutic agents can be administered concurrently or sequentially. The antihormonal agents and optional chemotherapeutic agents are administered according to their protocols, dosage amounts, and dosage forms that are well know to those skilled in the art (e.g., the Physician's Desk Reference or published literature). For example, for Tamoxifen, Fulvestrant, Raloxifene, Anastrozole, Letrozole, Exemestane, Leuprolide and Goserelin, see the Physician's Desk Reference, 57th Edition, 2003, published by Thomas PDR at Montvale, N.J. 07645-1742, the disclosure of which is incorporated herein by reference thereto. RECIEVED IPONZ 22 AUGUST 2011 -181 - In general, in the embodiments directed to the methods of treating Breast Cancer: (1) the compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 161) can be administered daily (e.g., once per day, and in one embodiment twice a day), (2) the aromatase inhibitors can be administered in 5 accordance with the known protocol for the aromatase inhibitor used (e.g., once per day), (3) the antiestrogens can be administered in accordance with the known protocol for the antiestrogen used (e.g., from once a day to once a month), (4) the LHRH analogue can be administered in accordance with the known protocol for the LHRH analogue used (e.g., once a month to once every three months), and (5) the 10 chemotherapeutic agent can be administered in accordance with the known protocol for the chemotherapeutic agent used (e.g., from once a day to once a week). Radiation therapy, if administered in the above treatments for breast cancer, is generally administered according to known protocols before administration of the compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 15 1 to 161), antihormonal agents and optional chemotherapeutic agents. Treatment according to the methods of treating breast cancer is continuous (i.e., a continuous dosing schedule is followed). The treatment is continued until there is a complete response, or until the skilled clinician determines that the patient is not benefiting from the treatment (for example, when there is disease progression). 20 The continuous treatment protocol for breast cancer can be changed to a discontinuous treatment schedule if, in the judgment of the skilled clinician, the patient would benefit from a discontinuous treatment schedule with one or more of the administered drugs. For example, the compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 161) can be given using a 25 discontinous treatment schedule while the remaining drugs used in the treatment are given as described herein. An example of a discontinuous treatment protocol for the compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 161) is a repeating cycle of three weeks with the compound of formula 1.0 followed by one week without the compound of formula 1.0. 30 After a complete response is achieved with the breast cancer treatment, maintenance therapy with the compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 161) can be continued using the dosing described in the methods discussed herein. Maintenance therapy can also include administration of the antihormonal agents using the dosing described in the methods RECIEVED IPONZ 22 AUGUST 2011 -182- discussed herein. Maintenance therapy can just be with the antihormonal agents. For example, after a complete response is achieved, an aromatase inhibitor (e.g., Anastrozole, Letrozole or Exemestane) can be continued for up to five years. Or, for example, an antiestrogen, e.g., Tamoxifen, may be used for up to five years after a 5 complete response is achieved. Or, for example, an antiestrogen (e.g., Tamoxifen) can be used for up to five years after a complete response is achieved followed by the use of an aromatase inhibitor (e.g., Anastrozole, Letrozole or Exemestane) for up to five years. In the embodiments directed to the treatment of breast cancer described 10 above, the compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 161) is administered continuously in a total daily dose of about 100 mg to about 600 mg. Usually this amount is administered in divided doses, and in one embodiment this amount is administered twice a day. In one embodiment the compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 15 1 to 161) is dosed twice a day in an amount of about 50 mg to about 300 mg per dose. In another embodiment the compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 161) is dosed twice a day in an amount of about 100 mg to about 200 mg per dose. Examples include the compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 161) 20 being dosed twice a day at 100 mg per dose. Examples also include the compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 161) being dosed twice a day at 200 mg per dose. Anastrozole is administered p.o. and is dosed once a day in amounts of about 0.5 to about 10 mg per dose, and in one embodiment in an amount of about 1.0 mg 25 per dose. Letrozole is administered p.o. and is dosed once a day in amounts of about 1.0 to about 10 mg per dose, and in one embodiment in an amount of about 2.5 mg per dose. Exemestane is administered p.o. and is dosed once a day in amounts of about 30 10 to about 50 mg per dose, and in one embodiment in an amount of about 25 mg per dose. Fadrozole is administered p.o. and is dosed twice a day in amounts of about 0.5 to about 10 mg per dose, and in one embodiment in an amount of about 2.0 mg per dose. RECIEVED IPONZ 22 AUGUST 2011 -183- Formestane is administered i.m. and is dosed once every two weeks in amounts of about 100 to about 500 mg per dose, and in one embodiment in an amount of about 250 mg per dose. Tamoxifen is administered p.o. and is dosed once a day in amounts of about 5 10 to about 100 mg per dose, and in one embodiment in an amount of about 20 mg per dose. Fulvestrant is administered i.m. and is dosed once a month in amounts of about 100 to about 1000 mg per dose, and in one embodiment in an amount of about 250 mg per dose. 10 Raloxifene is administered p.o. and is dosed once a day in amounts of about 10 to about 120 mg per dose, and in one embodiment in an amount of about 60 mg per dose. Acolbifene is administered p.o. and is dosed once a day in amounts of about 5 to about 20 mg per dose, and in one embodiment in an amount of about 20 mg per 15 dose. Goserelin is administered s.c. and is dosed once a month, or once every three months, in amounts of about 2 to about 20 mg per dose, and in one embodiment in an amount of about 3.6 mg per dose when administered once a month, and in another embodiment in an amount of about 10.8 mg per dose when administered 20 once every three months. Leuprolide is administered s.c. and is dosed once a month, or once every three months, in amounts of about 2 to about 20 mg per dose, and in one embodiment in an amount of about 3.75 mg per dose when administered once a month, and in another embodiment in an amount of about 11.25 mg per dose when administered 25 once every three months. Trastuzumab is administered by i.v. and is dosed once a week in amounts of about 2 to about 20 mpk per dose, and in one embodiment in an amount of about 2 mpk per dose. Trastuzumab is generally initially administered in a loading dose that is generally twice the dose of the weekly dose. Thus, for example, a 4 mpk loading 30 dose is administered and then dosing is 2 mpk per dose per week. Gefitinib is administered p.o. and is dosed once a day in amounts of about 100 to about 1000 mg per dose, and in one embodiment in an amount of about 250 mg per dose. RECIEVED IPONZ 22 AUGUST 2011 -184- Erlotinib is administered p.o. and is dosed once a day in amounts of about 100 to about 500 mg per dose, and in one embodiment in an amount of about 150 mg per dose. Bevacizumab is administered i.v. and is dosed once every two weeks in amounts of about 2.5 to about 15 mg per kilogram of body weight per dose, and in one embodiment in an amount of about 10 mg per kilogram per dose. Cetuximab is administered i.v. and is dosed once a week in amounts of about 200 to about 500 mg per meter squared dose, and in one embodiment in an amount of about 250 mg per meter squared per dose. Bortezomib is administered i.v. and is dosed twice a week for 2 weeks followed by a 10 day rest period (21 day treatment cycle) for a maximum of 8 treatment cycles in amounts of about 1.0 to about 2.5 mg per meter squared per dose, and in one embodiment in an amount of about 1.3 mg per meter squared per dose. Thus in one embodiment breast cancer is treated (or prevented) in a patient in need of such treatment wherein said treatment comprises administering to said patient: (1) the compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 161) orally in an amount of about 50 mg to about 300 mg per dose wherein each dose is administered twice a day, and (2) Anastrozole p.o. in an amount of about 0.5 to about 10 mg per dose wherein each dose is given once a day. In another embodiment breast cancer is treated (or prevented) in a patient in need of such treatment wherein said treatment comprises administering to said patient: (1) the compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 161) orally in an amount of about 100 to 200 mg per dose, wherein each dose is administered twice a day, and (2) Anastrozole in an amount of about 1.0 mg per dose wherein each dose is given once a day. In another embodiment breast cancer is treated (or prevented) in a patient in need of such treatment wherein said treatment comprises administering to said patient: (1) the compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 161) orally in an amount of about 50 mg to about 300 mg per dose wherein each dose is administered twice a day, and (2) Letrozole p.o. in an amount of about 1.0 to about 10 mg per dose wherein each dose is given once a day. In another embodiment breast cancer is treated (or prevented) in a patient in need of such treatment wherein said treatment comprises administering to said patient: (1) the compound of formula 1.0 (for example, as described in any one of RECIEVED IPONZ 22 AUGUST 2011 -185- Embodiment Nos. 1 to 161) orally in an amount of about 100 to 200 mg per dose, wherein each dose is administered twice a day, and (2) Letrozole p.o. in an amount of about 2.5 mg per dose wherein each dose is given once a day. In another embodiment breast cancer is treated (or prevented) in a patient in 5 need of such treatment wherein said treatment comprises administering to said patient: (1) the compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 161) orally in an amount of about 50 mg to about 300 mg per dose wherein each dose is administered twice a day, and (2) Exemestane p.o. in an amount of about 10 to about 50 mg per dose wherein each dose is given once a day. 10 In another embodiment breast cancer is treated (or prevented) in a patient in need of such treatment wherein said treatment comprises administering to said patient: (1) the compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 161) orally in an amount of about 100 to 200 mg per dose, wherein each dose is administered twice a day, and (2) Exemestane in an amount of 15 about 25 mg per dose wherein each dose is given once a day. In another embodiment breast cancer is treated (or prevented) in a patient in need of such treatment wherein said treatment comprises administering to said patient: (1) the compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 161) orally in an amount of about 50 mg to about 300 mg per 20 dose wherein each dose is administered twice a day, and (2) Fulvestrant i.m. in an amount of about 100 to about 1000 mg per dose wherein each dose is given once a month. In another embodiment breast cancer is treated (or prevented) in a patient in need of such treatment wherein said treatment comprises administering to said 25 patient: (1) the compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 161) orally in an amount of about 100 to 200 mg per dose, wherein each dose is administered twice a day, and (2) Fulvestrant i.m. in an amount of about 250 mg per dose wherein each dose is given once a month. In another embodiment breast cancer is treated (or prevented) in a patient in 30 need of such treatment wherein said treatment comprises administering to said patient: (1) the compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 161) p.o. in an amount of about 50 mg to about 300 mg per dose wherein each dose is administered twice a day, and (2) Tamoxifen p.o. in an RECIEVED IPONZ 22 AUGUST 2011 -186 - amount of about 10 to about 100 mg per dose wherein each dose is given once a day. In another embodiment breast cancer is treated (or prevented) in a patient in need of such treatment wherein said treatment comprises administering to said 5 patient: (1) the compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 161) p.o. in an amount of about 100 to 200 mg per dose, wherein each dose is administered twice a day, and (2) Tamoxifen p.o. in an amount of about 20 mg per dose wherein each dose is given once a day. In other embodiments breast cancer is treated in a patient in need of such 10 treatment wherein said treatment comprises the administration of the compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 161), one of the aromatase inhibitors (e.g., Anastrozole, Letrozole, or Exemestane, and in one embodiment Anastrozole), and one of the antiestrogens (e.g., Fulvestrant or Tamoxifen), wherein the compound of formula 1.0, aromatase inhibitor and 15 antiestrogen are administered in the dosages described above. Thus, for example in another embodiment breast cancer is treated (or prevented) in a patient in need of such treatment wherein said treatment comprises administering to said patient: (1) the compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 161) p.o. in an amount of about 50 mg 20 to about 300 mg per dose wherein each dose is administered twice a day, (2) Anastrozole p.o. in an amount of about 0.5 to about 10 mg per dose wherein each dose is given once a day, and (3) Fulvestrant i.m. in an amount of about 100 to about 1000 mg per dose wherein each dose is given once a month. In another embodiment breast cancer is treated (or prevented) in a patient in 25 need of such treatment wherein said treatment comprises administering to said patient: (1) the compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 161) p.o in an amount of about 100 to 200 mg per dose, wherein each dose is administered twice a day, (2) Anastrozole p.o. in an amount of about 1.0 mg per dose wherein each dose is given once a day, and (3) Fulvestrant 30 i.m. in an amount of about 250 mg per dose wherein each dose is given once a month. In another embodiment breast cancer is treated (or prevented) in a patient in need of such treatment wherein said treatment comprises administering to said patient: (1) the compound of formula 1.0 (for example, as described in any one of RECIEVED IPONZ 22 AUGUST 2011 -187- Embodiment Nos. 1 to 161) p.o. in an amount of about 50 mg to about 300 mg per dose wherein each dose is administered twice a day, (2) Letrozole p.o in an amount of about 1.0 to about 10 mg per dose wherein each dose is given once a day, and (3) Fulvestrant in an amount of about 100 to about 1000 mg per dose wherein each dose 5 is given once a month. In another embodiment breast cancer is treated (or prevented) in a patient in need of such treatment wherein said treatment comprises administering to said patient: (1) the compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 161) p.o. in an amount of about 100 to 200 mg per dose, 10 wherein each dose is administered twice a day, (2) Letrozole p.o. in an amount of about 2.5 mg per dose wherein each dose is given once a day, and (3) Fulvestrant i.m. in an amount of about 250 mg per dose wherein each dose is given once a month. In another embodiment breast cancer is treated (or prevented) in a patient in 15 need of such treatment wherein said treatment comprises administering to said patient: (1) the compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 161) p.o. in an amount of about 50 mg to about 300 mg per dose wherein each dose is administered twice a day, (2) Exemestane p.o. in an amount of about 10 to about 50 mg per dose wherein each dose is given once a day, 20 and (3) Fulvestrant i.m. in an amount of about 100 to about 1000 mg per dose wherein each dose is given once a month. In another embodiment breast cancer is treated (or prevented) in a patient in need of such treatment wherein said treatment comprises administering to said patient: (1) the compound of formula 1.0 (for example, as described in any one of 25 Embodiment Nos. 1 to 161) p.o. in an amount of about 100 to 200 mg per dose, wherein each dose is administered twice a day, (2) Exemestane p.o. in an amount of about 25 mg per dose wherein each dose is given once a day, and (3) Fulvestrant i.m. in an amount of about 250 mg per dose wherein each dose is given once a month. In another embodiment breast cancer is treated (or prevented) in a patient in 30 need of such treatment wherein said treatment comprises administering to said patient: (1) the compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 161) p.o. in an amount of about 50 mg to about 300 mg per dose wherein each dose is administered twice a day, (2) Anastrozole p.o. in an amount of about 0.5 to about 10 mg per dose wherein each dose is given once a day, RECIEVED IPONZ 22 AUGUST 2011 -188- and (3) Tamoxifen p.o.in an amount of about 10 to about 100 mg per dose wherein each dose is given once a day. In another embodiment breast cancer is treated (or prevented) in a patient in need of such treatment wherein said treatment comprises administering to said 5 patient: (1) the compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 161) p.o. in an amount of about 100 to 200 mg per dose, wherein each dose is administered twice a day, (2) Anastrozole p.o. in an amount of about 1.0 mg per dose wherein each dose is given once a day, and (3) Tamoxifen p.o. in an amount of about 20 mg per dose wherein each dose is given once a day. 10 In another embodiment breast cancer is treated (or prevented) in a patient in need of such treatment wherein said treatment comprises administering to said patient: (1) the compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 161) p.o. in an amount of about 50 mg to about 300 mg per dose wherein each dose is administered twice a day, (2) Letrozole p.o. in an amount 15 of about 1.0 to about 10 mg per dose wherein each dose is given once a day, and (3) Tamoxifen p.o. in an amount of about 10 to about 100 mg per dose wherein each dose is given once a day. In another embodiment breast cancer is treated (or prevented) in a patient in need of such treatment wherein said treatment comprises administering to said 20 patient: (1) the compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 161) p.o. in an amount of about 100 to 200 mg per dose, wherein each dose is administered twice a day, (2) Letrozole p.o. in an amount of about 2.5 mg per dose wherein each dose is given once a day, and (3) Tamoxifen p.o. in an amount of about 20 mg per dose wherein each dose is given once a day. 25 In another embodiment breast cancer is treated (or prevented) in a patient in need of such treatment wherein said treatment comprises administering to said patient: (1) the compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 161) p.o. in an amount of about 50 mg to about 300 mg per dose wherein each dose is administered twice a day, (2) Exemestane p.o. in an 30 amount of about 10 to about 50 mg per dose wherein each dose is given once a day, and (3) Tamoxifen p.o. in an amount of about 10 to about 100 mg per dose wherein each dose is given once a day. In another embodiment breast cancer is treated (or prevented) in a patient in need of such treatment wherein said treatment comprises administering to said RECIEVED IPONZ 22 AUGUST 2011 -189- patient: (1) the compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 161) p.o. in an amount of about 100 to 200 mg per dose, wherein each dose is administered twice a day, (2) Exemestane p.o. in an amount of about 25 mg per dose wherein each dose is given once a day, and (3) Tamoxifen p.o. 5 in an amount of about 20 mg per dose wherein each dose is given once a day. Those skilled in the art will appreciate that when other combinations of antihormonal agents are used, the individual antihormonal agent is used in the amounts specified above for that individual antihormonal agent. Other embodiments of the treatment of Breast Cancer are directed to the 10 methods of treating Breast Cancer described above wherein the compound of formula 1.0 (for example, as described in any one of Embodiment Nos. 1 to 161) is dosed twice a day in an amount of about 100 mg per dose. Other embodiments of the treatment of Breast Cancer are directed to the methods of treating Breast Cancer described above wherein the compound of formula 15 1.0 (for example, as described in any one of Embodiment Nos. 1 to 161) is dosed twice a day in an amount of about 200 mg per dose. Other embodiments of the treatment of Breast Cancer are directed to the methods of treating Breast Cancer described above wherein a chemotherapeutic agent is administered in addition to the compound of formula 1.0 (for example, as 20 described in any one of Embodiment Nos. 1 to 161) and antihormonal agent (or antihormonal agents). In these embodiments the dosage ranges of the compound of formula 1.0 and antihormonal agents are as those described above in the combination therapies, or those described above for the individual compound of formula I and antihormonal agents, and the dosages of the chemotherapeutic agents 25 are those described above for the individual chemotherapeutic agent. The dosages for the chemotherapeutic agents are well known in the art. Other embodiments of this invention are directed to pharmaceutical compositions comprising the compound of formula 1.0 of the invention (for example, as described in any one of Embodiment Nos. 1 to 161) and at least one antihormonal 30 agent and a pharmaceutically acceptable carrier. Other embodiments of this invention are directed to pharmaceutical compositions comprising the compound of formula 1.0 of the invention (for example, as described in any one of Embodiment Nos. 1 to 161), at least one antihormonal RECIEVED IPONZ 22 AUGUST 2011 -190- agent, at least one chemotherapeutic agent, and a pharmaceutically acceptable carrier. Other embodiments of this invention are directed to pharmaceutical compositions comprising the compound of formula 1.0 of the invention (for example, 5 as described in any one of Embodiment Nos. 1 to 161), at least one chemotherapeutic agent, and a pharmaceutically acceptable carrier. Those skilled in the art will appreciate that the compounds (drugs) used in the methods described herein, and uses of the invention are available to the skilled clinician in pharmaceutical compositions (dosage forms) from the manufacturer and 10 are used in those compositions. So, the recitation of the compound or class of compounds in the above described methods, and uses of the invention can be replaced with a recitation of a pharmaceutical composition comprising the particular compound or class of compounds. For example, the embodiment directed to a method of treating cancer comprising administering to a patient in need of such 15 treatment therapeutically effective amounts of the compound of formula 1.0, a taxane, and a platinum coordination compound, includes within its scope a method of treating cancer comprising administering to a patient in need of such treatment therapeutically effective amounts of a pharmaceutical composition comprising the compound of formula 1.0, a pharmaceutical composition comprising a taxane, and a 20 pharmaceutical composition comprising a platinum coordination compound. Those skilled in the art will recognize that the actual dosages and protocols for administration employed in the methods described herein and uses of the invention may be varied according to the judgment of the skilled clinician. The actual dosage employed may be varied depending upon the requirements of the patient and the 25 severity of the condition being treated. Determination of the proper dosage for a particular situation is within the skill of the art. A determination to vary the dosages and protocols for administration may be made after the skilled clinician takes into account such factors as the patient's age, condition and size, as well as the severity of the cancer being treated and the response of the patient to the treatment. 30 The amount and frequency of administration of the compound of formula 1.0 and the chemotherapeutic agents will be regulated according to the judgment of the attending clinician (physician) considering such factors as age, condition and size of the patient as well as severity of the cancer being treated. RECIEVED IPONZ 22 AUGUST 2011 -191 - The chemotherapeutic agent can be administered according to therapeutic protocols well known in the art. It will be apparent to those skilled in the art that the administration of the chemotherapeutic agent can be varied depending on the cancer being treated and the known effects of the chemotherapeutic agent on that disease. Also, in accordance with the knowledge of the skilled clinician, the therapeutic protocols (e.g., dosage amounts and times of administration) can be varied in view of the observed effects of the administered therapeutic agents on the patient, and in view of the observed responses of the cancer to the administered therapeutic agents. The initial administration can be made according to established protocols known in the art, and then, based upon the observed effects, the dosage, modes of administration and times of administration can be modified by the skilled clinician. The particular choice of chemotherapeutic agent will depend upon the diagnosis of the attending physicians and their judgement of the condition of the patient and the appropriate treatment protocol. The determination of the order of administration, and the number of repetitions of administration of the chemotherapeutic agent during a treatment protocol, is well within the knowledge of the skilled physician after evaluation of the cancer being treated and the condition of the patient. Thus, in accordance with experience and knowledge, the practicing physician can modify each protocol for the administration of an chemotherapeutic agent according to the individual patient's needs, as the treatment proceeds. All such modifications are within the scope of the present invention. The particular choice of antihormonal agents, optional chemotherapeutic agents and optional radiation will depend upon the diagnosis of the attending physicians and their judgment of the condition of the patient and the appropriate treatment protocol. The determination of the order of administration, and the number of repetitions of administration of the antihormonal agents, optional chemotherapeutic agents and optional radiation during a treatment protocol, is well within the knowledge of the skilled physician after evaluation of the breast cancer being treated and the condition of the patient. Thus, in accordance with experience and knowledge, the practicing physician can modify each protocol for the administration of antihormonal agents, optional chemotherapeutic agents and optional radiation according to the individual patient's RECIEVED IPONZ 22 AUGUST 2011 -192 10 needs, as the treatment proceeds. All such modifications are within the scope of the present invention. The attending clinician, in judging whether treatment is effective at the dosage administered, will consider the general well-being of the patient as well as more definite signs such as relief of cancer-related symptoms (e.g., pain, cough (for lung cancer), and shortness of breath (for lung cancer)), inhibition of tumor growth, actual shrinkage of the tumor, or inhibition of metastasis. Size of the tumor can be measured by standard methods such as radiological studies, e.g., CAT or MRI scan, and successive measurements can be used to judge whether or not growth of the tumor has been retarded or even reversed. Relief of disease-related symptoms such as pain, and improvement in overall condition can also be used to help judge effectiveness of treatment. The compounds of the invention can be made according to the processes 15 described below. / ivnv tmsch2n2 HO I Boc i R2 1B Scheme 1 MeO VpN R2 2B TFA Boc "HO MeO I NH R2 3B 20 25 bciju k2co3/dmf MeO R2 4B MeO J ^^ OH 5B TFA R? O The appropriately substituted pyrrolidine is prepared as follows. The methyl ester of pyrrolidine 1B is prepared by reaction with TMSdiazomethane. After removing the BOC protecting group, compound 3B is reacted with bromo-tert.butylacetate to obtain 4B. The tert.butyl ester is then removed to obtain intermediate 5B. Scheme 2 RECIEVED IPONZ 22 AUGUST 2011 -193- The R5 substituted piperazine is prepared by Buchwald type coupling of the piperazine 6B with an aryl bromide in the presence of palladium to obtain the piperazine 7B. The BOC group is removed using acidic conditions (e.g., TFA) to give piperazine 7C. Scheme 3 Y1—Y2 Y1rY2 hn—i. ')—N°i reduction H i-.j —~\\ })—nh2 Br 8B Br gg The indazole bromide 9B is prepared by reduction of the indazole nitro compound 8B using reducing conditions such as palladium on carbon in the presence of hydrogen atmosphere. A R2 5B O 0H Coupling agent RECIEVED IPONZ 22 AUGUST 2011 -194- Y1_Y2 h NH2 ro i i Br 9B R2 JL v Coupling agent ^5 11B Rs" VX^R5 r4 o Y1-Y2 R/^^( R RiB(OH)2 \ 126 R3^ -x. DME7H2O N' Y'N6 PdCI2dppf/Na2C03 \ r4 r5 The final molecule is assembled by coupling the pyrrolidine 5B with the piperazine (X is N, see compound 7C from Scheme 2), or with the piperidine (X is C, prepared in Schemes 11 or 12, or prepared according to the Examples described 10 herein, or prepared according to methods well known to those skilled in the art), using standard coupling conditions such as HATU in DMF to obtain 10B. After hydrolysis of the methyl ester to obtain 11B, the indazole intermediate 9B is then coupled using standard coupling conditions such as HATU in DMF to obtain 12B. The indazole is then derivatized at the 3 position by suzuki coupling with an a boronic acid to obtain 15 the final product 13B. RECIEVED IPONZ 22 AUGUST 2011 5 -195-Scheme 5 y1=y2 y1=y2 hn /v-no2 sem_c| se\^ /v-no2 i v—y3 i y—y3 N-^/ Pd coupling Br 8B Br 14B Y1-y2 y1=y2 seivi / \ sem / \ N—Vv /) no2 N-^Vv /) NH2 I y—y3 reduction / >—y3 n^/ ► N^/ r1 15B r1 16B HVp-ANJLR6 Ro I I 2 o 11B *3 T ^R5 x. y1-y2 HN ^ tf /\—N /? * ^ H *1 ' •v k2 n /r6 \ Coupling agent A Followed by SEM deprotection □ „00 _ x ^1 IOD K3 R4 R5 Alternatively, the final product 13B can be prepared by protecting the indazole 8B as the SEM (or trityl) derivative followed by Suzuki coupling to give the 10 appropriately substituted indazole intermediate 15B. After reduction using reducing conditions such as palladium on carbon in the presence of hydrogen atmosphere to obtain 16B, the amine 16B can be coupled to 11B using standard coupling conditions such as HATU in DMF to obtain 13B. 15 RECIEVED IPONZ 22 AUGUST 2011 -196 - Scheme 6 3-Amirio substituted indazole derivatives can be prepared according to general Scheme 6 by coupling the Boc protected 3,5-diamino indazole 17B with 11B under standard coupling conditions such as HATU in DMF to obtain 18B. The 3-amino group can then be reacted with acid chlorides, sulfonyl chlorides and isocyanates to prepare the corresponding amides, sulfonamides and ureas 19B respectively. Those skilled in the art will appreciate that the moiety -NHXA represents the amino substituted R1 groups, such as, -N(R10)2, -NR32-C(0)-R14, -N(R10)C(O)N(R10)2, and -N(R10)S(O)tR10. Scheme 7 acid chloride sulfonyl chloride R isocyanate RECIEVED IPONZ 22 AUGUST 2011 -197- O The amino methyl indazole derivative 20B can be prepared according to Example 76 step 1 through 4 by substituting the appropriately substituted rings. The 3-aminomethyl group can then be reacted with acid chlorides, sulfonyl chlorides and 5 isocyanates to prepare the corresponding amides, sulfonamides and ureas 21B respectively. Those skilled in the art will appreciate that the moiety -CH2NHXB represents the amino substituted methyl R1 groups, such as, -(C(R30)2)n-NR32-C(O)-R10 (wherein n is 1 and each R30 is H), -(C(R30)2)n-NR32-S(O)t-R10 (wherein n is 1 and each R30 is 10 H), -(C(R30)2)n-NR32-C(O)-N(R32)-R10 (wherein n is 1 and each R30 is H), -(C(R30)2)nR13 (wherein n is 1, each R30 is H and R13 is -N(R10)2), Scheme 8 15 HN^\ XCNH Coupling agent The amide compound 23B can be prepared by following Example 87 substituting the appropriate compound 11B (General Scheme 4). The resulting acid RECIEVED IPONZ 22 AUGUST 2011 -198- 22B is then coupled with the appropriate amine under standard coupling conditions such as in the presence of EDC/HOBt to obtain 23B. Those skilled in the art will appreciate that the moiety -C(0)NHXc represents the amide R1 groups, such as, -C(O)N(R10)2 and -C(0)-NR32-C(R18)3 CI £ no2 24 B h H2, Pd/C h2n xu h r4 Scheme 9 ci Pd(PPh3)2CI2, to I no2 25B n,h 2n4 oon h r4 15 Indazoles of type 27B can be prepared by reacting 24B with the appropriately substituted acetylene in the presence of Pd(PPh3)2CI2 in toluene to obtain 25B. After heating with hydrazine to obtain 26B, 27B is obtained after hydrogenation. Coupling RECIEVED IPONZ 22 AUGUST 2011 -199- of 27B with 11B under standard coupling conditions such as HATU or EDC/HOBt gives 28B. The moiety -CH2XD represents R1 groups that are an R10 substituent, such as, alkyl, heteroarylalkyl, and arylalkyl. Scheme 10 (Me)3Si ^^N^^OMe 29B ^Ph H2 9 —c-z4 = R2 The appropriately substituted pyrrolidine 32B can be obtained by reacting 29B with the appropriately substituted compound 30B in the presence of trifluoroacetic acid to obtain 31B. Compound 31B can then be deprotection under hydrogenation conditions (Pd/C, H2 to obtain 32B). C02Et .z4 30B Alternative Process For Scheme 10 1) IDA r-A TFA Et02CvJ ^NBoc ► Et02CsvJ[ /NBoc ► Et02Cssl NH 2) E 33B CL 34B I „ 32B Z4 z 4 (E = electrophile) Alternatively, 32B can be obtain by reaction 33B with LDA followed by the addition of a suitable electrophile such as allylbromide, as in example 127, to obtain 34B. Treatment of 34B with trifluoroacetic acid yields 32B. RECIEVED IPONZ 22 AUGUST 2011 -200- Scheme 11 PdCI2(dppf), potassium phosphate dioxane ► Ar1-XE Ar1= aryl, heteroaryl XE = Br or CI TFA H2, Pd/C 38B Aryl or heteroaryl substituted piperidines can be prepared by Suzuki coupling of an aryl or heteroaryl halide with the pinicolboronate 34B to obtain 35B. The ring double bond can then be hydrogenated to obtain 36B followed by removal of the Boc protecting group under trifluoroacetic acid conditions. Alternatively the double bond can be retained and the Boc group removed to give 38B. Similarly aryl or heteroaryl substituted piperizines with a 2 carbon spacer can be prepared as shown in Scheme 12 by coupling an aryl or heteroaryl halide with an acetylene derivative 39B that can be prepared according to procedures known in the RECIEVED IPONZ 22 AUGUST 2011 -201 - 10 15 20 art to obtain 40B. 40B can then be reduced to 41B followed by by removal of the Boc protecting group under trifluoroacetic acid conditions. Alternatively the Boc protecting group from 40B can be removed under trifluoroacetic acid conditions to give 43B. Compounds of this invention are exemplified in the following examples, which should not be construed as limiting the scope of the disclosure. Alternative mechanistic pathways and analogous structures within the scope of the invention may be apparent to those skilled in the art. The LCMS conditions are: (1) column: C-18 reverse phase, 5um, 4.6 x 50 mm, (2) MS:PE Sciex API-150EX, and (3) HPLC; Shimadzu LC-10 ADvp, 1ml/min, linerar gradient 10% acetonitirle in water to 95% acetonitrile in water, both contain 0.05% TFA R-pyrrolidine-1,3-dicarboxylic acid 1 -tert-butyl ester (2.15 gm, 10 mmol) was dissolved in 12 ml of toluene and 3.5 ml of methanol. Trimethylsilyldiazomethane 2N solution in hexanes( 6.56 ml, 13.12 mmol) was added dropwise and the reaction mixture stirred for 2 hours. The mixture was evaporated to obtain 2.1 gm of an oil. The oil was dissolved in dichloromethane (15 ml) and 5 ml of 4N hydrochloric acid in dioxane added. The reaction mixture was stirred for 1 hr and evaporated to give an oil that crystallizes to give 1.68 gm of title product. RECIEVED IPONZ 22 AUGUST 2011 -202- 10 15 20 Step 2 Preparation of 1-tert-Butoxycarbonylmethyl-pyrrolidine-3-carboxylic acid methyl ester R-pyrrolidine-3-carboxylic acid methyl ester (1.5 gm, 9.1 mmol) was dissolved in N,N-dimethylformamide (45 ml). Diisopropylethylamine (5.7 ml, 31 ml) was added followed by cesium carbonate (4.35 gm, 13.3 mmol). Tert. butylbromoacetate (1.5 ml, 10 mmol) was added dropwise and the reaction mixture stirred for 1 hr. Brine was added to the reaction mixture which was then extracted with ethylacetate three times. The ethylacetate extracts were dried over magnesium sulfate, filtered and evaporated to obtain crude title product. The crude product was chromatographed to obtain 2.15 gm, 97% of title product. Step 3 Preparation of 1-Carboxymethyi-pyrrolidine-3-carboxyiic acid methyl ester R-1-tert-Butoxycarbonylmethyl-pyrrolidine-3-carboxylic acid methyl ester ( 2.15 gm, 8.8 mmol) was dissolved in 20 ml of 50% trifluoroacetic acid/dichloromethane and stirred for 2 hrs. The reaction mixture was evaporated to an oil and exchanged with hydrochloric acid by dissolving in 20 ml of dichloromethane and adding 10 ml of 1N HCI in ether to obtain 3.35 gm of a gummy solid. Step 4 Preparation of 4-(4-Bromo-phenyl)-piperazine-1-carboxylic acid tert-butyl ester 6 RECIEVED IPONZ 22 AUGUST 2011 -203- 1-(4-Bromo-pheriyl)-piperazirie hydrochloride( 9 gm, 38 mmol) was dissolved in 250 ml of dichloromethane and 9 ml of triethylamine added. Di-tert.butyldicarbonate (8.34 gm, 39 mmol) was added and the reaction mixture stirred for 1 hr. The reaction mixture was washed with a solution of saturated sodium bicarbonate (100 ml), the 5 organic layer separated, dried over magnesium sulfate and evaporated to obtain 10.19 gm of crystalline product. Preparation of 4-(4-boronic acid-phenyl)-piperazine-1-carboxylic acid tert-butyl 10 ester 4-(4-Bromo-phenyl)-piperazine-1-carboxylic acid tert-butyl ester (10.19 gm, 30 mmol) was dissolved in 26 ml of tetrahydrofuran. The mixture was cooled to -78 C under a dry nitrogen atmosphere. A 2.5 N solution nButyl lithium in hexanes (26 ml, 15 65 mmol) was added dropwise and stirred for 30 min. Triisopropylborate ( 14.68 ml, 63.6 mmol) was added over 10 min. and the reaction mixture let warm to ambient temperature gradually. The reaction mixture was stirred for 18 hrs. A saturated solution of Ammonium chloride (75 ml) was added and the reaction mixture stirred for 5 min. 85% o-Phosphoric acid (7.27 gm) was added and the reaction mixture stirred 20 for 1 hr. The reaction mixture was extracted with ethylacetate three times, dried over magnesium sulfate, filtered and evaporated. The crude product was chromatographed on a silica column to obtain 5.74 gm of title product. Step 6 25 Preparation of 4-(4-Pyrimidin-2-yl«phenyi)-piperazine-1-carboxylic acid tert-butyl Step 5 7 H ester Boc Boc^ I 8 RECIEVED IPONZ 22 AUGUST 2011 -204- 4-(4-boronic acid-phenyl)-piperazine-1-carboxylic acid tert-butyl ester (5.93 gm, 19.3 mmol) was dissolved in 50 ml of a 50% mixture of N,N-dimethylformamide/water. K2C03 (16 gm) was added and the mixture de-gased and purged with nitrogen. Pd (dppf)2CI2 (1.57 gm) and 2-chloropyrimidine (2.72 gm) was added and the reaction 5 mixture stirred at 80 C. After 8 hours the product was extracted into ethylacetate, dried over magnesium sulfate, filtered and evaporated. The crude product was chromatographed on silica gel to obtain 5.03 gm (76.6%) of title product. 10 15 20 Step 7 Preparation of 2-(4-Piperazin-1-yl-phenyl)-pyrimidine Boc. ¥ 1 -n 4-(4-Pyrimidin-2-yl-phenyl)-piperazine-1-carboxylic acid tert-butyl ester 5.03 gm was dissolved in 25 ml dichloromethane and 10 ml of 4N HCI dioxane added. After stirring for 2 hrs, the mixture was then evaporated to obtain the title product. Step 8 Preparation of 1-{2-Oxo-2-[4-(4-pyrimidin-2-yl-phenyl)-piperazin-1-yl]-ethyl}-pyrrolidine-3-carboxylic acid methyl ester o. 10- 25 2-(4-Piperazin-1-yl-phenyl)-pyrimidine (compound 10 from Step 7, 14.7 mmol) and 1-Carboxymethyl-pyrrolidine-3-carboxylic acid methyl ester (compound 5 from Step 3, 17.6 mmol) were dissolved in 72 ml of DMF. Triethylamine ( 8 ml, 57 mmol), 1-hydroxybenztriazole ( 2.29 gm ) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) (3.43 gm, 18 mmol) were added and the reaction mixture stirred for 24 hrs. After washing with brine, extracting with dichloromethane, and RECIEVED IPONZ 22 AUGUST 2011 -205- drying over magnesium sulfate, the mixture was evaporated and chromatographed on silica gel to obtain 5.0 gm of title product. Step 9 5 Preparation of 1 -{2-Oxo-2-[4-(4-pyrimidin-2-yl-phenyl)-piperazin-1 -yl]-ethyl}- pyrrolidine-3-carboxylic acid 10 1 -{2-Oxo-2-[4-(4-pyrimidin-2-yl-phenyl)-piperazin-1 -yl]-ethyl}-pyrrolidine-3- carboxylic acid methyl ester (compound 11 from Step 8, 3.3 gm, 8.06 mmol) was dissolved in methanol and 10 ml of 1N lithium hydroxide added. The reaction mixture was stirred for 18 hrs. 10 ml of 1N HCI was added to the reaction mixture and evaporated to a white solid (3.94 gm) 15 Step 10 Preparation of 1 -{2-Oxo-2-[4-(4-pyrimidin-2-yl-phenyl)-piperazin-1 -yl]-ethyl}-pyrrolidine-3-carboxylic acid [3-(4-fluoro-phenyl)-1 H-indazol-5-yl]-amide RECIEVED IPONZ 22 AUGUST 2011 -206- H h 12 + OJL f f 3-(4-Fluoro-phenyl)-1H-indazol-5-ylamine ( 0.11gm, 0.5 mmol) and 1-{2-Oxo-2-[4-(4-pyrimidin-2-yl-phenyl)-piperazin-1-yl]-ethyl}-pyrrolidine-3-carboxylic acid (compound 12 from Step 9, 0.125 gm, 0.25 mmol) were dissolved in 4 ml of DMF. O-(7-azabenzotriazol-1-yl-)-N,N,N,N-tetramethyluronium hexafluorophosphate (HATU) (0.24 gm, 0.63 mmol) and triethylamine (0.1 ml, 0.76 mmol) were added to the reaction mixture and the mixture stirred for 18 hrs. The reaction mixture was added to bring and extracted with dichloromethane. After drying over magnesium sulfate and filtered, the mixture was evaporated and chromatographed to obtain 36.7 mg of title product. Bromide 15 (4.2 g, 17.4 mmol, prepared according to procedure of Barbet, Eur. J. Med. Chem. Chim. Ther.; Fr; 21; 4; 1986, 359) and stannous chloride hydrate (17.0 g, 75.3 mmol) were dissolved in EtOH (35 mL). The crude was stirred at 70 "C for 2.5 hrs. The crude was cooled to rt and poured into ice water (50 ml). The PH was made basic via addition of 15% wt NaOH (100 mL). The aq layer was extracted with EtOAc. The EtOAc layer was dried over MgS04, filtered, and evaporated to give 1.82 g of the crude product. h 15 16 Step 2 Preparation of 1 -{2-Oxo-2-[4-(4-pyrimidin-2-yl-phenyl)-piperazin-1 -yl]-ethyl}1 -pyrrolidine-3-carboxylic acid (3-bromo-1H-indazol-5-yl)-amide RECIEVED IPONZ 22 AUGUST 2011 -207- Crude 3-bromo-1 H-indazol-5-ylamine 16 (403 mg, 1.9 mmol) and carboxylic acid 12 from Example 1 Step 9 (357 mg, 0.90 mmol) were dissolved in CH2CI2 (3 mL) 5 and DMF (3 ML). To the crude was added triethylamine (1.01 mL), and HATU (722 mg, 1.9 mmol). The crude was stirred at rt for 5 hrs under a stream of nitrogen. To the crude was added additional portions of 3-bromo-1 H-indazol-5-ylamine 16 (300 mg, 1.42 mmol), HATU (500 mg, 1.32 mmol), and diisopropylethylamine (0.3 mL). To the crude was added CH2CI2 (5 mL) and DMF (3 ML). The crude was stirred 10 overnight under a stream of nitrogen. The crude was quenched with sat. NaHC03 at rt. The crude was diluted in EtOAc. The organic layer was washed with water, brine, dried over Na2S04, filtered, and evaporated. The crude was chromatographed to give 367 mg of the product. 15 Step 3 Preparation of 1 -{2-Oxo-2-[4-(4-pyrimidin-2-yl-phenyl)-piperazin-1 -yl]-ethyl}-pyrrolidine-3-carboxylic acid[3-(3-cyano-phenyl)-1H-indazol-5-yl]-amide ,B(OH)2 rf t 17 + // ^ 18 To a solution of bromide 17 from Step 2 (107 mg, 0.18 mmol) in DME (2 mL) 20 and distilled water (0.5 mL) in a 5 mL conical microwave reaction vessel was added boronic acid (107 mg, 0.73 mmol), Na2C03 (100 mg, 0.94 mmol), and PdCI2dppf (59 mg, 0.072 mmol). The crude was sealed with reaction vessel cap. The crude was heated at 120 "C in an EMRY optimizer microwave for 600 sees. The crude was cooled and quenched with water at rt. The aq layer was extracted with CH2CI2. The 25 organic layer was dried over Na2S04j filtered, and evaporated. The crude was RECIEVED IPONZ 22 AUGUST 2011 -208- purified via prep plate to give 55 mg of the product. LC Mass Spec M + 1 (pretention time: 612.1@3.17 EXAMPLES 3 to 60 Following a procedure similar to that of Example 2, compound 17 was reacted with R1B(OH)2 to prepare, via the microwave Suzuki reaction, the compound 19: wherein R1 is defined in Table 1. In Table 1 "Ex" represents "Example". Table 1 I* el LCMass Soec M+1 (5) ret. time 3 *0 587 @ 3.61 mi 4 5 617.1@2.86 min 6 V*i RECIEVED IPONZ 22 AUGUST 2011 -209- 7 647.2 @ 2.83 8 CI 9 c OMe Vi N 10 *CO 11 *<x, 612.1 @ 3.09 12 576.3 @2.5 13 629.3 @ 2.57 14 15 VrF ^T)Me 16 N OMe RECIEVED IPONZ 22 AUGUST 2011 -210 - 17 N 18 N OMe 19 OH 603.1 @2.87 20 /NCN N 21 r s / 0 635.2 @ 3.13 22 'tX 23 o o 24 /C^/^OMe 617.1 @3.24 25 605.1 @ 3.24 26 HN^O 644.2 @ 2.87 RECIEVED IPONZ 22 AUGUST 2011 -211 - 27 *xx 601.1 @ 3.29 28 /x? 29 *0. 601.1 @2.81 30 631.2 @ 3.13 31 601.1 @ 3.27 32 629.1 @3.02 33 594 @ 3.35 34 /^c, 621.1 @ 3.40 35 ^NO, 632.1 @ 3.31 36 >rc*o 645.2 @ 3.22 37 V F RECIEVED IPONZ 22 AUGUST 2011 -212- 38 CSl o 632.1 @3.29 39 "xx. 615.1 @ 3.24 40 655.1 @ 3.48 41 621.1 @3.38 42 S02M6 652 @2.97 43 "6 605.1 @2.94 44 N 594 @ 3.13 45 CO LL O < 655.1 @3.48 46 629.1 @3.51 47 48 RECIEVED IPONZ 22 AUGUST 2011 -213- 49 /Y1 ^^NCOCH3 644,1 @ 3.54 50 629.1 @3.56 51 CD iA 647.2 @2.9 52 /JL 621.1 @2.73 53 Me ifn 601.1 @3.13 54 629.1 @2.98 55 623.1 @3.08 56 , NAc (Ac = CH3C(0)-) 644.2 @2.85 57 c CF3 yS 655.1 @3.38 58 C02Me 645.2 @3.05 RECIEVED IPONZ 22 AUGUST 2011 -214- 59 & CD 617.1 @2.83 60 *6 605.1 @2.94 EXAMPLE 61 Step 1 5 Preparation of 3-Bromo-5-nitro-1 -trityi-1 H-indazole Br Br. 15 20 To a solution of 15 (3.8 g, 15.7 mmol) in CH3CN (100 mL) was added potassium carbonate (10.42 g, 75.4 mmol) followed by the addition of TrCI (15.9 g, 10 56.4 mmol) at rt for 48 h. The solvent was evaporated and the crude was dissolved in CH2CI2. The crude was quenched with water. The aq. layer was extracted with CH2CI2. The combined organic layer was washed with H20, brine, dried over MgS04, filtered, and evaporated. The solid crude was placed onto a filter funnel and washed with 20% EtOAc / hexane (1 L) and 5% EtOAc / hexane (500 mL). The crude solid 15 was collected from the filter and dried overnight to afford 7 g of the product. Step 2 Preparation of 5-Nitro-1-trityl-3-(1-trityl-1H-imidazol-4-yl)-1 H-indazole nBuiSn NTr 21 20 20 A solution of 21 (2.73 g, 6.19 mmol, prepared according to Jetter, M. C.; Reitz, A. B. Synthesis, 1998, 829-831), bromide 36 (0.73 g, 2.07 mmol) and Pd(PPh)4 (474 RECIEVED IPONZ 22 AUGUST 2011 -215- mg, 0.41 mmol) in toluene (10 mL) was heated at 100 X) under an atmosphere of nitrogen for 18 hrs. The crude was cooled, evaporated, and chromatographed to provide 730 mg of the product. Step 3 Preparation of 1 -Trityl-3-(1 -trityl-1 H-imidazol-4-yl)-1 H-indazol-5-ylamine To a solution of 22 (730 mg, 1.02 mmol g, 17.4 mmol) in MeOH (150 mL) was added 10% wt Pd/C (700 mg). The crude was capped with a 3-way stopcock with connections to both vaccum and also a balloon of hydrogen gas. The crude was degassed using house vacuum and represurrized with hydrogen gas. The process was repeated 5X. The crude was stirred under an atmosphere of hydrogen at rt for 3 hrs. The crude was filtered through a microfiber filter. The filtrate was evaporated and used in the following reaction without further purification. Step 4 Preparation of 3-(1H-lmidazol-4-yl)-1H-indazol-5-ylamine To a solution of ylamine 23 (crude 420 mg, 1.02 mmol) in CH2CI2 (8 mL) and H20 (1 mL) was added TFA (1 mL) at rt. The crude was stirred at rt for 60 hrs. The crude was quenched with sat. NaHCC>3 at rt. The crude was evaporated and filtered through a plug of Na2SC>4. The crude was evaporated and purified via preparation plates to give 120 mg of the product. RECIEVED IPONZ 22 AUGUST 2011 -216- Step 5 Preparation of 1 -{2-Oxo-2-[4-(4-pyrimidin-2-yl-phenyl)-piperazin-1 -yl]-ethyl}-pyrrolidine-3-carboxylic acid [3-(1 H-imidazoI-4-yl)-1 H-indazol-5-yl]-amide 5 Amine 24 (82 mg, 0.41 mmol) and carboxylic acid 12 (81 mg, 0.21 mmol) were dissolved in CH2CI2 (2 mL) and DMF (2 ML). To the crude was added TEA (1.16 mL), and HATU (156 mg, 0.41 mmol). The crude was stirred at rt for 22 hrs under a stream of nitrogen. The crude was quenched with sat. NaHC03 at rt and filtered over a plug of silica gel. The crude was evaporated and purified via preparation plates to 10 give 17 mg of the product. EXAMPLE 62 Step 1 Preparation of 3-Bromo-5-nitro-1 -(2-trimethylsi!anyl-ethoxymethyl)-1 H-indazole vXA NO2 V^\^NO2 Br Br 15 15 26 To a solution of 15 (7.9 g, 32.6 mmol) in DMF (163 mL) was added 60% wt NaH (2.0 g, 49 mmol) portionwise over 5 mins at rt. The crude was stirred at rt for 30 mins before the addition of SEMCI (7.5 mL, 42.4 mmol) at rt. The crude was stirred at rt for 58 hrs. The crude was quenched with H20 and diluted in EtOAc. The aq. layer 20 was extracted with EtOAc 3X. The combined organic layer was washed with H20, brine, dried over MgS04, filtered, and evaporated. The crude was chromatographed to give 7.4 g of the product. RECIEVED IPONZ 22 AUGUST 2011 -217- Step 2 Preparation of 5-Amino-1 -(2-trimethylsilanyl-ethoxymethyl)-1 H-indazole-3-carbonitrile SEM N SEM N 26 27 To a solution of bromide 26 (550 mg, 1.34 mmol) in DMF (5 mL) in a 10 mL microwave reaction vessel was added ZnCN2 (160 mg, 1.34 mmol), and PdCI2dppf (320 mg, 0.39 mmol). The crude was sealed with reaction vessel cap. The crude was heated at 180 "C in an EMRY optimizer microwave for 1800 sees. The crude was cooled and quenched with water at rt. The crude was diluted in EtOAc and washed with H20 3X. The organic layer was dried over Na2S04, filtered, and evaporated. The crude was chromatographed to give 150 mg of the product. Step 3 Preparation of 5-Amino-1 -(2-trimethylsi!anyl-ethoxymethyl)-1 H-indazole-3-carbonitrile SEM SEM To a solution of nitrile 27 (150 mg, 0.47 mmol) in EtOAc (5 mL) was added 10% wt Pd/C (30 mg). The crude was capped with a 3-way stopcock with connections to both vaccum and also a balloon of hydrogen gas. The crude was degassed using house vacuum and represurrized with hydrogen gas. The process was repeated 5X. The crude was stirred at rt for 4 hrs. The crude was filtered through a microfiber filter. The filtrate was evaporated and purified via preparation plate to give 70 mg of the product. RECIEVED IPONZ 22 AUGUST 2011 -218- Step 4 Preparation of 1 -{2-Oxo-2-[4-(4-pyrimidin-2-yl-phenyl)-piperazin-1 -yl]-ethyl}-pyrrolidine-3-carboxylic acid [3-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1 H-indazol-5-yl]-amide SEM ^ r^r^N->i^V ^ I I 1 O 12 + 29 Amine 28 (242 mg, 0.84 mmol) and carboxylic acid 12 (162 mg, 0.42 mmol) were dissolved in CH2CI2 (2 mL) and DMF (2 ML). To the crude was added DIPEA (0.3 mL, 1.68 mmol), and HATU (326 mg, 0.84 mmol). The crude was stirred at rt for 18 hrs under a stream of nitrogen. The crude was quenched with sat. NaHC03 at rt. 10 The crude was diluted in EtOAc. The organic layer was washed with water, brine, dried over Na2S04, filtered, and evaporated. The crude was chromatographed to give 212 mg of the product. Step 5 15 Preparation of 1 -{2-Oxo-2-[4-(4-pyrimidin-2-yl-phenyl)-piperazin-1 -yl]-ethyl}-pyrrolidine-3-carboxylic acid (3-cyano-1H-indazol-5-yl)-amide o 29 ► HN ^ 30 To a solution of 29 (20 mg, 0.03 mmol) in CH2CI2 (2 mL) was added TFA (2 mL) at rt. The crude was stirred at rt for 18 hrs. The crude was evaporated and 20 quenched with sat. NaHC03 at rt. The crude was evaporated and filtered through a plug of silica gel and evaporated. The crude was purified via preparation plate to give 13 mg of the product. RECIEVED IPONZ 22 AUGUST 2011 -219- EXAMPLE 63 Step 1 Preparation of 1-{2-Oxo-2-[4-(4-pyrimidin-2-yl-phenyl)-piperazin-1-yl]-ethyl}-pyrrolidine-3-carboxylic acid [3-(1 H-tetrazol-5-yl)-1 -(2-trimethylsilanyl-5 ethoxymethyl)-1 H-indazol-5-yl]-amide 29 ► O -V, " N. ',N N^J N To a solution of 29 from Example 62 Step 4 (40 mg, 0.061 mmol) in DMF was added NaN3 (12 mg, 0.18 mmol) and NH4CI (13 mg, 0.24 mmol). The crude was stirred at 100 *0 for 18 hrs. The crude was cool, evaporated, and filtered through a 10 plug of cotton. The crude was evaporated and purified via preparation plate to give 31 mg of a mixture of two isomers. Step 2 Preparation of 1-{2-Oxo-2-[4-(4-pyrimidin-2-yl-phenyl)-piperazin-1-yl]-ethyl}-15 pyrrolidine-3-carboxylic acid [3-(1 H-tetrazol-5-yl)-1 H-indazol-5-yl]-amide n-a¥-C"-^o N! ,,N N^J N To a solution of 31 from Step 1 (31 mg, 0.054 mmol, 2 isomers) in CH2CI2 (2 mL) was added TFA (2 mL) at rt. The crude was stirred at rt for 5 hrs. The crude was evaporated and quenched with sat. NaHC03 at rt. The crude was evaporated and 20 filtered through a plug of silica gel and evaporated. The crude was purified via preparation plate to give 13 mg of the product. RECIEVED IPONZ 22 AUGUST 2011 -220- EXAMPLE 64 Step 1 Preparation of 5-[(1 -{2-Oxo-2-[4-(4-pyrimidin-2-yl-phenyl)-piperazin-1 -yl]-ethyl}-pyrrolidine-3-carbonyl)-amino]-1-(2-trimethylsilanyl-ethoxymethyl)-1 H-indazole-3-carboximidic acid 29 To a solution of nitrile 29 from Example 63 Step 4 (40 mg, 0.06 mmol) in EtOH (0.4 mL) was added DIPEA (0.1 mL, 0.6 mmol) and NH2OH.HCI (21 mg, 0.3 mmol) at rt. The crude was stirred at 45 "C for 18 hrs. Th e crude was cooled, evaporated, and filtered through a plug of cotton. The crude was evaporated and purified via preparation plate to give 18 mg of the product. Step 2 Preparation of 5-[(1 -{2-Oxo-2-[4-(4-pyrimidin-2-yl-phenyl)-piperazin-1 -yl]-ethyl}-pyrrolidine-3-carbonyl)-amino]-1 H-indazole-3-carboximidic acid o 33 0 k^N 34 To a solution of 33 from Step 1 (18 mg, 0.03 mmol) in CH2CI2 (2 mL) was added TFA (2 mL) at rt. The crude was stirred at rt for 5 hrs. The crude was evaporated and quenched with sat. NaHC03 at rt. The crude was evaporated and filtered through a plug of silica gel and evaporated. The crude was purified via preparation plate to give 18 mg of the product. RECIEVED IPONZ 22 AUGUST 2011 -221 - EXAMPLE 65 Step 1 Preparation of 3-Amino-5-[(1 -{2-oxo-2-[4-(4-pyrimidin-2-yl-phenyl)-piperazin-1 -yl]-ethyl}-pyrrolidine-3-carbonyl)-amino]-indazole-1 -carboxylic acid tert-butyl ester 03/064397) in CH2CI2 (5 mL) and DMF (3 ML) was added carboxylic acid 12 from Example 1 Step 9 (375 mg, 0.95 mmol), diisopropylethylamine (0.4 mL, 2.28 mmol), and HATU (433 mg, 1.14 mmol). The crude was stirred overnight at rt under a stream of nitrogen. To the crude was added additional portions of amine 35 (283 mg, 1.14 mmol), HATU (433 mg, 1.14 mmol), and diisopropylethylamine (0.4 mL, 2.28 mmol). To the crude was added CH2CI2 (5 mL) and DMF (3 ML). The crude was stirred at rt for a total of 85 hrs under a stream of nitrogen. The crude was quenched with sat. NaHC03 at rt. The crude was diluted in EtOAc. The organic layer was washed with water, brine, dried over Na2S04, filtered, and evaporated. The crude was chromatographed to give 410 mg of the product. Step 2 Preparation of 3-Acetylamino-5-[(1-{2-oxo-2-[4-(4-pyrimidin-2-yl-phenyl)-piperazin-1 -yl]-ethyl}-pyrrolidine-3-carbonyl)-amino]-indazole-1 -carboxylic acid tert-butyl ester o 36 ► „ J 8 O 37 o- To a solution of 36 from Step 1 in CH2CI2 (0.3 mL) and pyridine (0.3 mL) was added acetyl chloride (50 ul, 0.7 mmol) at rt. The crude was stirred at rt for 30 mins. RECIEVED IPONZ 22 AUGUST 2011 -222- The crude was quenched with sat. NaHC03 at rt. The crude was partitioned between EtOAc and H20. The organic layer was washed with H20, brine, dried over MgS04, filtered, and evaporated. The crude was chromatographed to give 20 mg of the product. Step 3 Preparation of 1 -{2-Oxo-2-[4-(4-pyrimidin-2-yl-phenyl)-piperazin-1 -yl]- ethyl}-pyrrolidine-3-carboxylic acid (3-acetylamino-1 H-indazol-5-yl)-amide - n N 37 ^ 0 38 nh oA To a solution of 37 from Step 2 (20 mg, 0.03 mmol)37 in CH2CI2 (2 mL) was added TFA (2 mL) at rt. The crude was stirred at rt for 17 hrs. The crude was quenched with sat. NaHC03 at rt. The crude was partitioned between EtOAc and H20. The organic layer was washed with H20, brine, dried over MgS04, filtered, and evaporated. The crude was chromatographed to give 6.1 mg of the product. RECIEVED IPONZ 22 AUGUST 2011 -223- / / TFA \ X1 / 40a 40b \ I (TFA = Trifluoroacetic acid) I Compound 36 was used to prepare compounds of formula 40b wherein X1 is defined in Table 2. To obtain the desired X1 substitutent, Compound 36 is reacted with X1's corresponding commercially available acid chloride, isocyanate or sulfonyl chloride. The BOC group is then removed with trifluoroacetic acid. In Table 2 "Ex" represents "Example". TABLE 2 Ex x: LCMass Spec M+1 (S> ret. time 66 H 526.1 @2.13 67 JWUWW 0^ 630.1 @2.71 68 vA/WVW -S7 594.3 @2.12 69 O^ ^ 596.3 @2.15 70 v/WW\ 645.4 @2.60 RECIEVED IPONZ 22 AUGUST 2011 -224- 71 >AAAAAA, I 02S^ 604.3 @2.10 72 JWVWV 597.3 @2.20 73 awww O^NH2 669.3 @1.98 EXAMPLE 74 Step 1 Preparation of 3-Morpholin-4-yl-5-nitro-1 H-indazole 3-Bromo-5-nitro-1 H-indazole ( 0.5 gm, 2 mmol) was dissolved in 3.5 ml of morpholine and heated in a sealed tube for 40 hrs. The mixture was then cooled and added to ethylacetate, washed with brine and dried over magnesium sulfate. After chromatography on silica gel using 20-50% ethylacetate/hexanes as eluent the title compound was obtained (210 mg, 0.85 mmol). Step 2 Preparation of 3-Morpholin-4-yl-1H-indazol-5-ylamine 3-Morpholin-4-yl-5-nitro-1 H-indazole (210 mg) was dissolved in 10 ml of methanol and the mixture hydrogenated at 1 atm of hydrogen using 10% Pd/C (50 RECIEVED IPONZ 22 AUGUST 2011 -225- mg) as catalyst. After 24 hrs, the mixture was filtered and evaporated for use in the next step. Step 3 Preparation of 1 -{2-Oxo-2-[4-(4-pyrimidin-2-yl-phenyl)-piperazin-1 -yI]-ethyl}-pyrrolidine-3-carboxylic acid (3-morpholin-4-yl-1 H-indazol-5-yl)-amide The title compound was prepared following the procedure in Example 1 Step 10 except amine 42 from Step 2 was used instead of amine 13. EXAMPLE 75 Preparation of 1 -{2-Oxo-2-[4-(4-pyrimidin-2-yl-phenyl)-piperazin-1 -yl]-ethyl}-pyrrolidine-3-carboxylic acid (3-pyrroiidin-1 -yl-1 H-indazol-5-yl)-amide 44 The title compound was prepared following the procedures in Example 74, Steps 1 and 2, and Example 1, Step 10, by using pyrrolidine instead of morpholine in Example 74, Step 1. The amine prepared following the procedure of Example 76, Steps 1 and 2, is used instead of amine 13 in the procedure of Example 1, Step 10 . RECIEVED IPONZ 22 AUGUST 2011 -226- EXAMPLE 76 10 15 20 Step 1 Preparation of 3-Bromomethyl-5-nitro-indazole-1 -carboxylic acid tert-butyl ester 3-Methyl-5-nitro-1 H-indazole ( 1.89 gm, 10.2 mmol) was dissolved in 20 ml of acetonitrile. A catalytic amount of DMAP followed by triethylamine (2.13 ml, 1.5 eq) and di-tert.butyldicarbonate (2.88 gm, 1.3 eq) was added and stirred for 3 hrs. The reaction mixture was evaporated to dryness and dissolved in ethyl acetate and washed with 0.1 N HCI. The ethyl acetate layer was washed twice with water, dried over magnesium sulfate and chromatographed on silica gel to give a 2.05 gm of Boc compound. The entire amount of Boc compound was dissolved in 20 ml of CCI4 and benzoylperoxide ( 179 mg, 0.74 mmol) and N-bromosuccinimide ( 1.45 gm, 8.14 mmol) were added. The reaction mixture was refluxed for 2 hrs. After 2 hrs 179 mg of benzoylperoxide was added and the reaction mixture refluxed for 18 hrs. The reaction mixture was cooled and washed with water and dried over magnesium sulfate. After chromatography on silica gel, 1.32 gm of title product was obtained. Step 2 Preparation of 2-(5-Nitro-1 H-indazol-3-ylmethyl)-isoindole-1,3-dione 3-Bromomethyl-5-nitro-indazole-1-carboxylic acid tert-butyl ester (0.63g, 1.77 mmol) and potassium phthalimide (0.396g, 1.2 eq) were stirred in DMF (1 mL) at 80 ■C for two hours. TLC (20% EtOAc/hexane) showed starting material consumed and new products formed. After DMF was evaporated, a residue, 1.33g, was obtained. Br RECIEVED IPONZ 22 AUGUST 2011 -227- The resulting residue was stirred in DCM and filtered. The filtration cake then washed with DCM followed by hexane. The evaporation of the filtrate gave 0.79g of crude. Flash chromatograph (20 - 30 % EtOAc/hexane) gave a mixture, two spots shown on TLC. During the sample preparation, solid precipitated and the solid was collected, 5 95 mg. MS showed de-Boc product, (M+H)+ at 323. An adequate amount of this mixture was treated with TFA in DCM for two hours. TLC showed one spot and MS gave (M+H)+at 323. The remaining mixture was stirred in a mixture of TFA (6 mL) and DCM (10 mL) for two hours. Evaporation of TFA and DCM gave the desired product, 0.71 g, (quant, yield). 2-(5-Nitro-1H-indazol-3-ylmethyl)-isoindole-1,3-dione (0.71 gm) was dissolved 15 in methanol and hydrogenated at 1 atm. using 10% Pd/C (catalytic) for 18 hrs. The catalyst was filtered and the mixture evaporated to obtain 614 mg of title product. Step 4 Preparation of 1 -{2-Oxo-2-[4-(4-pyrimidin-2-yl-phenyl)-piperazin-1 -yl]-ethyl}-20 pyrrolidine-3-carboxylic acid [3-(1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-1H-indazol-5-yl]-amide 10 Step 3 Preparation of 2-(5-Amino-1 H-indazol-3-ylmethyl)-isoindole-1,3-dione 49 + 12 0 50 RECIEVED IPONZ 22 AUGUST 2011 -228- 2-(5-Amino-1H-indazol-3-ylmethyl)-isoindole-1,3-dione (compound 49 from Step 3, 614 gm, 2 mmol) and compound 12 (from Example 1 Step 9) were dissolved in 10 ml of DMF. 0-(7-azabenzotriazol-1-yl-)-N,N,N,N-tetramethyluronium hexafluorophosphate (HATU) (660 mg, 1.7 mmol) and diisopropylethylamine ( 0.9 ml, 5 eq.). After stirring 4 hours, the reaction mixture was added to brine and extracted with ethylacetate, dried over magnesium sulfate and evaporated. The crude was chromatographed on silica gel to obtain 440mg of title product. EXAMPLE 77 Preparation of 1 -{2-Oxo-2-[4-(4-pyrimidin-2-yl-phenyl)-piperazin-1 -yl]-ethyl}-pyrrolidine-3-carboxylic acid (3-aminomethyl-1 H-indazol-5-yl)-amide /YV O^N0N 50 ° N=( 51 H2N 1-{2-Oxo-2-[4-(4-pyrimidin-2-yl-phenyl)-piperazin-1-yl]-ethyl}-pyrrolidine-3-carboxylic acid [3-(1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-1 H-indazol-5-yl]-amide (compound 50 from Example 78, 424 mg, 0.633 mmol) was dissolved in ethanol and 0.31 ml of hydrazine hydrate. The mixture was heated at 80 C for 20 hrs and then evaporated to dryness. The mixture was chromatographed on silica gel to obtain 100 mg of title product. RECIEVED IPONZ 22 AUGUST 2011 -229- EXAMPLES 78 TO 84 Following a procedure similar to that of Examples 66 to 73 compound 51 (from Example 77) was used to prepare compounds of formula 52 wherein X2 is defined in Table 3. To obtain the desired final compound in Examples 78, 80 and 81, 5 Compound 51 is reacted with X2's corresponding commercially available acid chloride. To obtain the desired final compound in Example 79, 83 and 84 Compound 51 is reacted with X2's corresponding commercially available isocyanate. To obtain the desired final compound in Example 82, Compound 51 is reacted with X2's corresponding to commercially available sulfonyl chloride. In Table 3 "Ex" represents 10 "Example". Table 3 I* xf 78 -C(0)CH3 79 -C(0)NH2 80 3Y 81 oH RECIEVED IPONZ 22 AUGUST 2011 -230- 82 02S^ 83 84 EXAMPLE 85 Step 1 Preparation of 5-Nitro-1H-indazole-3-carboxylic acid (54) To a suspension of indazole-3-carboxylic acid (compound 53, 3.0 g, 18 mmol) in 18 mL of concentrated sulfuric acid at 0 C was added potassium nitrate (2.0 g, 18 10 mmol). The reaction was stirred overnight at room temperature, poured into 150 mL of ice and extracted three times with ethyl acetate. The combined organic layer was washed with brine, dried and concentrated to give compound 54 (2.9 g) as the major isomer. 15 RECIEVED IPONZ 22 AUGUST 2011 -231 - Step 2 Preparation of 5-Nitro-1H-indazole-3-carboxylic acid methylamide (55) To a solution of compound 54 (100 mg, 0.483 mmol), methylamine hydrochloride (52.2 mg, 0.773 mmol), HOBt (130 mg, 0.966 mmol) and DIEA (0.34 5 mL, 1.95 mmol) in N-methylpyrrolidinone was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (148 mg, 0.773 mmol). The reaction was stirred at room temperature for 2 hrs and diluted with 10 mL of ethyl acetate. The mixture was washed with water and a yellow solid precipitated. The precipitate was collected by filtration to give compound 55 (67 mg). 10 Step 3 Preparation of 5-Amino-1H-indazole-3-carboxylic acid methylamide (56) To a suspension of compound 55 (65 mg) in 5 mL of methanol was added catalytic amount of 5% palladium on carbon. The mixture was stirred under a 15 hydrogen atmosphere at room temperature for 4 hrs and filtered through celite. The filtrate was concentrated to afford compound 56 (59 mg). To a suspension of indazole-3-carboxylic acid (3.0 g, 18 mmol) in 18 mL of concentrated sulfuric acid at 0 C was added potassium nitrate (2.0 g, 18 mmol). The reaction was stirred overnight at room temperature, poured into 150 mL of ice and extracted three times with ethyl acetate (90 mL total). The combined organic layer 25 was washed with brine, dried and concentrated to give (54) (2.9 g) as the major product. 30 Step 2 EXAMPLE 86 Step 1 20 53 54 RECIEVED IPONZ 22 AUGUST 2011 -232 - '2 Boc N HO u N02 HO ^O 54 55a To a solution of compound 54 (230 mg, 1.11 mmol) in 5mL of THF was added sodium hydroxide solution (1 M, 3.3 mL, 3.33 mmol), and then t-butyl dicarbonate (364 mg, 1.67 mmol). The reaction was stirred at room temperature overnight and treated with 3.4 mL of 1 N HCI. The mixture was extracted with ethyl acetate three times. The combined organic layer was dried over sodium sulfate and concentrated to provide compound 55a (307 mg). To a solution of compound 55a (307 mg, 1.00 mmol) was added N, N'-diisopropyl-f-butyl isourea (880 mg, 4.00 mmol). The reaction was heated to reflux overnight and filtered. The filtrate was concentrated and purified by column chromatography (3:1 hexane/ethyl acetate) to provide compound 56a (179 mg). To a mixture of compound 56a (150 mg, 0.413 mmol) in 5 mL of methanol was added catalytic amount of 5 % palladium on carbon. The mixture was stirred under a hydrogen atmosphere at room temperature overnight and filtered through celite. The filtrate was concentrated to provide compound 57 (98 mg). The material was used as such without further purification. Step 3 56a Step 4 RECIEVED IPONZ 22 AUGUST 2011 -233- Step 5 57+ 12 To a solution of compound 57, from Step 4, (98 mg, 0.29 mmol), 12 (TFA salt with LiCI, 211 mg, 0.29 mmol) 1-hydroxybenztriazole (40 mg, 0.29 mmol) and diisopropylamine (0.15 mL, 0.90 mmol) in DMF was added 1-(3-dimethylamino-propyl)-3-ethylcarbodiimide hydrochloride (EDCI) (73 mg, 0.38 mmol). The reaction was stirred overnight at room temperature for 2 hrs, concentrated and purified by reverse phase chromatography to give 58 as a TFA salt (180 mg). Compound 58, from Step 5, (180 mg, 0.192 mmol) was treated with TFA/DCM (3 mL/3mL) at room temperature. The reaction was stirred for 1 h and concentrated to provide 59 (115 mg). Step 6 58 TFA/DCM HN HO Step 7 RECIEVED IPONZ 22 AUGUST 2011 -234- 59 HATU, n-BuNH2, DMF To a solution of compound 59 (10 mg, 0.013 mmol) and n-butylamine (1.9 mg, 0.026mmol) in 1.5 mL of DMF was added HATU (14 mg). The reaction was stirred at room temperature for 2 hrs and concentrated. The residue was purified by reverse-phase chromatography to give 60 (5 mg). Step 1 To a suspension of indazole-3-carboxylic acid (compound 53, 3.0 g, 18 mmol) in 18 mL of concentrated sulfuric acid at 0 C was added potassium nitrate (2.0 g, 18 mmol). The reaction was stirred overnight at room temperature, poured into 150 mL of ice and extracted three times with ethyl acetate. The combined organic layer was RECIEVED IPONZ 22 AUGUST 2011 -235- washed with brine, dried and concentrated to give compound 54 (2.9 g) as the major isomer. Step 2 5 To a solution of compound 54 (100 mg, 0.483 mmol), methylamine hydrochloride (52.2 mg, 0.773 mmol), HOBt (130 mg, 0.966 mmol) and DIEA (0.34 mL, 1.95 mmol) in N-methylpyrrolidinone was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (148 mg, 0.773 mmol). The reaction was stirred at room temperature for 2 hrs and diluted with 10 mL of ethyl acetate. The mixture was 10 washed with water and a yellow solid precipitated. The precipitate was collected by filtration to give compound 55 (67 mg). Step 3 To a suspension of compound 55 (65 mg) in 5 mL of methanol was added 15 catalytic amount of 5% palladium on carbon. The mixture was stirred under a hydrogen atmosphere at room temperature for 4 hrs and filtered through celite. The filtrate was concentrated to afford compound 56 (59 mg). Step 4 20 Compound 56 was reacted with compound 12 (Example 1 Step 9) following the procedure of Example 1, Step 10, to prepare compound 61 Mass Spec.: 610, LCMS Retention Time 3.58 minutes. 25 EXAMPLES 88 TO 97 Compounds of formula 62 O >""On^L 62 RECIEVED IPONZ 22 AUGUST 2011 -236- wherein X3 is defined in Table 4 were prepared from compound 59 (from Example 86 Step 6) following a procedure similar to that described in Example 86 Step 7 and using the corresponding amine of X3. In Table 4 "Ex" represents "Example". 5 Table 4 §X x! Retention time (min) Mass Spec 88 •^NH 3.33 596 89 2.84 568 90 •^NH A 3.11 594 RECIEVED IPONZ 22 AUGUST 2011 -237 - 91 <^NH /° 2.42 612 92 <^NH a! 3.71 662 93 <^NH a1 2.44 645 94 <^NH OH 2.63 598 95 <^NH 0=0 NH, 2.54 611 96 o* "^NH 3.28 674 97 ^NH 6 3.72 630 RECIEVED IPONZ 22 AUGUST 2011 -238-EXAMPLE 98 Step 1 Preparation of 1 -tert-ButoxycarbonyImethyI-pyrrolidine-3-carboxylic acid,Lithium salt. 1-tert-Butoxycarbonylmethyl-pyrrolidine-3-carboxylic acid methyl ester 4 (see Example 1 Step 2) (0.753g, 3.098mmol) was dissolved in MeOH/THF (10ml;1/1) and 2N Lithium hydroxide (1.5ml; 3mmol) was added. The resultant solution was stirred for 2 hours, and solvent was evaporated yielding title compound 63 as a white solid 10 (0.71 g, 100%). Mass Spec ES (230,MH). Step 2 (HO)2B Pddppf.CI2 Na2C03 3-Bromo-5-nitro-1 H-indazole (Compound 15 (see Example 2 Step 2), 0.5g, 15 2.06mmol), 4-Flourophenylboronic acid (720mg, 5.14mmol), Pd(dppf)CI2 (252mg, 0.31 mmol), and Na2C03 (657mg, 6.20mmol) were added to a 25ml microwave vessel. DME (16ml) and H20 (4ml) were added subsequently. The mixture was heated under microwave at 150°C for 20 min. The reaction mixture was then filtered through a pad of celite. The filtrate was concentrated, and purified by flash column (25% 20 EtOAc/Hex) to yield Compound 64 (0.3g, 1.17mmol). RECIEVED IPONZ 22 AUGUST 2011 -239- Step 3 f 64 N02 Pd/C 10% f NH2 Compound 64 (0.57g, 2.22mmol) was dissolved in EtOAc (20ml) / MeOH (20ml). Pd/C (10 wt. %, cat.) was added. The mixture was subjected to 50PSI H2 on 5 a par apparatus at room temperature over night. The reaction was then filtered. The filtrate was concentrated to yield Compound 65 (492mg, 2.16mmol). Preparation of {3-[3-(4-Fluoro-phenyl)-1 H-indazol-6-ylcarbamoyl]-pyrrolidin-1 -yl}-10 acetic acid tert-butyl ester 1-tert-Butoxycarbonylmethyl-pyrrolidine-3-carboxylic acid,Lithium salt 63 (from Step 1) (665mg,2.83mmol) and N-Methyl morpholine (0.84ml,7.65mmol) were dissolved in THF (50ml) then cooled solution to 0 C. Isobutyl chloroformate 15 (0.37ml,2.83mmol) in THF (20ml) was added dropwise, and stirred at 0°C for 1 hour. 3-(4-Fluoro-phenyl)-1H-indazol-6-ylamine 65 (from Step 2) (576mg,2.54mmol) in THF (20ml) was added dropwise then stirred at room temperature for 1 hour. The reaction mixture was diluted with EtOAC (150ml), Water (60ml)and 5% NaOH (10ml).Organic layer was separated,dried over MgS04,and solvent evaporated yielding a residue 20 which was dissolved and stirred in Methanol(30ml) and 1N NaOH (10ml) for 10 minutes.Reaction was concentrated,residue extracted with EtOAc (200ml) washed with H20 (30ml),dried over Na2S04,filtered and concentrated yielding title compound 66 as a white solid (700mg, 63%). Step 4 f RECIEVED IPONZ 22 AUGUST 2011 -240- Step 5 Preparation of {3-[3-(4-Fluoro-phenyl)-1H-indazoI-6-ylcarbamoyI]-pyrrolidin-1-yl}-acetic acid trifluoroacetate. Compound 66 (700mg,1.60mmol) was stirred in trifluoroacetic acid (20%,10ml) for 2 hours,then the solvent was evaporated yielding the title compound as trifluoroacetate salt 67 as a white solid. (790mg,100%) ESMS (MH, 383). Step 6 Preparation of 2-(6-Bromo-pyridin-3-yI)-pyrimidine A mixture of 2-bromopyrimidine (0.43g,2.70mmol), 2-bromopyridine-5-boronic acid (0.55g,2.72mmol), tetrakis(triphenylphosphine)palladium(0) (300mg, 0.259mmol), cesium carbonate (1.15g, 3.03mmol) was stirred in MeOH/toluene/water (15ml, 1/1/1) at reflux temperature overnight. The reaction was cooled to room temperature and diluted with EtOAc (200ml) and water (50ml). The organic layer was separated, dried over MgS04,filtered and solvent evaporated yielding a residue which was purified on silica gel eluting with 25% v/vEtOAc/hexanes yielding product 76 as white solid. (0.55g, 85%) ESMS (MH, 236). F F HOv ,OH Br 76 RECIEVED IPONZ 22 AUGUST 2011 -241 - Step 7 Preparation of 2-(6-Piperazin-1-yl-pyridin-3-yl)-pyrimidine H -NN o N H K2C03/DMF 1 100°C A mixture of 2-(6-Bromo-pyridin-3-yl)-pyrimidine 76 (100mg, 0.425mmol), potassium carbonate (100mg,0.724mmol), and piperazine (100mg,1.16mmol) in DMF (5ml) were stirred at 100°C for 1 hour. The reaction was cooled,solvent evaporated under reduced pressure, and the residue dissolved in MeCI2 (150ml), washed with H20 (50ml),dried over MgS04,filtered and evaporated solvent yielding title product 77 as a white solid (100mg,98%). ESMS (MH, 242). Step 8 Preparation of 1 -{2-Oxo-2-[4-(5-pyrimidin-2-yl-pyridin-2-yl)-piperazin-1 -yl]-ethyl}-pyrrolidine-3-carboxylic acid [3-(4-fluoro-phenyl)-1 H-indazol-6-yl]-amide H I V O 77 + 67 EDCI, HOBT DMF, (C2H5)3N O I I 68 Added triethylamine (0.1ml, 0.7mmol) to solution of {3-[3-(4-Fluoro-phenyl)-1H-indazol-6-ylcarbamoyl]-pyrrolidin-1-yl}-acetic acid trifluoroacetate 67 (Step 5) (50mg, 0.1008mmol), 2-(6-Piperazin-1-yl-pyridin-3-yl)-pyrimidine 77 (Step 7) (60mg, 0.248mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) (50mg,0.261 mmol), 1-hydroxybenztriazole monohydrate (30mg,0.222mmol) in DMF (2ml), then stirred overnight at room temperature. The solvent was evaporated and residue purified on silica gel eluting with 7% v/v MeOH/MeCI2/NH4OH yielding product 68 as white solid (33mg, 54%). LCMS (MH, 606) Retention time = 2.46 minutes. RECIEVED IPONZ 22 AUGUST 2011 -242- EXAMPLES 99 TO 101 Following a procedure similar to that of Example 98, and using the appropriate reagents, the compounds in Table 5 were obtained. In Table 5 "Ex" represents 5 "Example". Table 5 Ex Compound Mass Spec LCMS MH Retention time Minutes 99 VGA-OA-, NT^ 0 N n f 620 2.45 100 VO-V^vA.-, NI 0 N=\ f 620 2.43 101 vpA"i£^ 1 x\ N=\ f|^| n n—^ f 647 3.23 EXAMPLE 102 10 Step 1 recieved iponz 22 august 2011 -243- Preparation of 1-Chloro-2-iodo-4-nitro-benzene ci nis,cf3so3h CI no2 68a no2 69 N-lodosuccinimide (1.71 g, 7.60mmol) was added to a solution of 1 -chloro-4-nitrobenzene (1.17g, 7.42mmol) in trifluoromethanesulfonic acid (10ml) at 0°C, then 5 stirred 1 hour at room temperature. The reaction was quenched with ice-water and extracted with MeCI2 (3x50ml). Organics were combined .washed with 10% sodium bisulfite (20ml) then dried over Na2S04, filtered and evaporated solvent yielding the title compound as a white solid (1.3g, 62%). 10 Step 2 Preparation of 1 -Chloro-2-(2-fluoro-phenylethynyl)-4-nitro-benzene Triethylamine (0.2ml, 1.43mmol) was added to a suspension of 1-Chloro-2-iodo-4-nitro-benzene 69 (Step 1) (100mg, 0.354mmol), 1-ethynyl-2-fluorobenzene 15 (100mg, 0.832mmol), copper iodide (100mg, 0.525mmol),Pd(PPh3)2CI2 (100mg, 0.142mmol) in dimethylformamide (2ml) at room temperature, then stirred at 70°C for 2 hours. Reaction was cooled to room temperature and extracted with ether (50ml), washed with water(20ml), dried (MgS04), filtered and solvent evaporated yielding a residue which chromatographed on silica gel eluting with 20% v/v MeCI2/hexanes 20 yielding title product 70 as pale yellow solid (80mg,82%). no2 69 recieved iponz 22 august 2011 -244 - Step 3 Preparation of 3-(2-Fluoro-benzyl)-5-nitro-1 H-indazole n2h4 BuOH Hydrazine.monohydrate (0.2ml, 4.1 mmol) was added to a solution of 1-chloro-2-(2-fluoro-phenylethynyl)-4-nitro-benzene 70 (Step 2) (80mg, 0.29mmol) in n-butanol (3ml) then refluxed for 2 hours. The mixture was cooled and solvent evaporated under reduced pressure. The residue was purified on silica gel eluting with 5% v/v MeOH/MeCI2 yielding product as yellow solid (60mg, 76%) ESMS (MH, 272). 10 Step 4 Preparation of 3-(2-Fluoro-benzyl)-1H-indazol-5-ylamine solution of 3-(2-fluoro-benzyl)-5-nitro-1 H-indazole (50mg,0.184mmol) in MeOH/THF 15 (3ml, 1 /1) then refluxed for 3 hours. The reaction was diluted with MeOH (20ml) and filtered through a celite pad. The solvent was evaporated, residue dissolved in MeCI2, dried over Na2S04,filtered and solvent evaporated yielding title compound as white solid (40mg, 88%) ESMS (MH, 242). RECIEVED IPONZ 22 AUGUST 2011 -245- Step 5 Preparation of 1 -{2-Oxo-2-[4-(4-pyrimidin-2-yl-phenyl)-piperazin-1 -yl]-ethyl}-pyrrolidine-3-carboxylic acid [3-(2-fluoro-benzyl)-1 H-indazol-6-yl]-amide EDCI.HCI 72+12 HOBT,NMM,DMF Added N-methylmorpholine (0.2ml) to solution of 3-(2-Fluoro-benzyl)-1H-indazol-5-ylamine 72 (Step 4) (5mg, 0.0207mmol), 1-{2-Oxo-2-[4-(4-pyrimidin-2-yl-phenyl)-piperazin-1-yl]-ethyl}-pyrrolidine-3-carboxylic acid 12 (see Example 1 Step 9) 10 (8mg, 0.0202mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) (5mg, 0.026mmol), 1-hydroxybenztriazole monohydrate (3mg, 0.022mmol) in DMF (2ml), then stirred overnight at room temperature. The solvent was evaporated and residue purified on silica gel eluting with 7% v/v MeOH/MeCl2/NH4OH yielding product as white solid (5mg,39%) ESMS (MH, 619). 15 EXAMPLES 103 TO 112 Following a procedure similar to that of Example 102, and using the appropriate reagents, compounds of formula 74: 20 74 wherein X4 is defined in Table 6 were prepared. The arrow indicates the point of attachment of the X4 substitutent to the rest of the molecule. No arrow is shown for recieved iponz 22 august 2011 -246- Example 109 because attachment to any of the carbons of the X4 phenyl group results in the same final compound of formula 74. In Table 6 "Ex" represents "Example". Table 6 5 I* X! Mass Spec (ESMS, MH) Retention time minutes 103 af 619 3.10 104 9 f 619 2.79 105 o " I 606 2.31 106 t if^l /k^\ f f 637 3.43 107 9 ch3 615 3.13 108 b och3 631 3.17 RECIEVED IPONZ 22 AUGUST 2011 -247- 109 0 601 2.70 110 602 2.36 t y 111 602 2.41 ♦ On 112 669 3.24 6 V cf3 EXAMPLES 113 to 118 Following a procedure similar to that of Example 102 and using the appropriate reagents, and using 1-{2-[4-(3-Chloro-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-pyrrolidine-3-carboxylic acid 75: ho o k .N 75 in place of 12, the compounds of formula 76: recieved iponz 22 august 2011 -248 0 76 wherein X5 is defined in Table 7 were prepared. The arrow indicates the point of attachment of the X5 substitutent to the rest of the molecule. In Table 7 "Ex" represents "Example". Table 7 Ex x! Mass Spec ESMS (MH) Retention time (minutes) 113 n 561 2.63 114 6 558 2.67 115 6" 575 3.40 116 i i 9 cf3 625 3.59 RECIEVED IPONZ 22 AUGUST 2011 -249 117 9 F 575 3.30 118 LL 575 3.52 EXAMPLE 119 Step 1 Preparation of 5-Methyl-2-[4-(3-(S)-methyl-piperazin-1 -yl)-phenyl]-pyrimidine H -N. N Pd (OAc)2 dbbp ► dioxane/H20 A mixture of 2-(4-bromophenyl)-5-methylpyrimidine 78 (250mg, 1.008mmol), palladium acetate (50mg), cesium carbonate (400mg,1.23mmol), (S)-2-methyl piperazine(200mg, 2mmol) and 2-Di-t-butylphosphino)-biphenyl (50mg, 0.167mmol) 10 was stirred in dioxane:water (10ml,v/v 5:1) at reflux temperature for 4 hours. The reaction was cooled,diluted with MeCI2 (100ml) and H20 (50ml). The organic layer was separated, dried (MgS04), filtered and solvent evaporated. The residue was purified by chromatography eluting with 100% EtOAc then with 10% v/v MeOH/EtOAc/NH4OH yielding product 79 as a white solid. (220mg.81%) ESMS (MH, 15 269). RECIEVED IPONZ 22 AUGUST 2011 -250 Step 2 Preparation of 1 -(2-{2-Methyl-4-[4-(5-methyl-pyrimidin-2-yl)-phenyl]-piperazin-1 -yl}-2-oxo-ethyl)-pyrrolidine-3-carboxylic acid [3-(4-fluoro-phenyl)-1 H-indazol-6-yl]-amide 79+ 67 EDCI.HOBT DMF, (C2H5)3N Following a procedure similar to that of Example 98, Step 8, but substituting 79 for 77, the title compound 80 was obtained as a white solid (ESMS, MH 633), Retention Time: 3.07 minutes. 10 EXAMPLES 120 TO 123 Following a procedure similar to that of Example 119, and using the appropriate reagent in place of 79 compounds of Examples 120, 121, and 123 in Table 8 were prepared, and the compound of Example 122 could be prepared. In Table 8 "Ex" represents "Example". 15 Table 8 Ex Compound Mass spec LCMS MH Retention time (minutes) 120 H H I \ O »>vCXa0 X~ ° W 633 3.45 F RECIEVED IPONZ 22 AUGUST 2011 -251 - 121 n ° ^ F 548 2.36 122 H / \ /—0 X ° /Wi \\ ^ S-^V-N T F 123 —Nl\ *0 S 0 ° vO--/^)_ F 647 3.23 EXAMPLE 124 Step 1 5 Preparation of 5-(4-Bromo-phenyl)-pyrimidin-2-ylamine Br Br Pd(PPh3)4 N^N CS2C03,Me0H/H20 B (0H)2 NH2 RECIEVED IPONZ 22 AUGUST 2011 -252- A mixture of 5-bromo-pyrimidin-2-ylamine (0.8g, 4.59mmol), 4-bromophenyl boronic acid(1g, 4.97mmol), tetrakis(triphenylphosphine)palladium(0) (300mg, 0.259mmol), cesium carbonate (1.15g, 3.03mmol) was stirred in Me0H/H20 (20ml, 1/1) at reflux temperature overnight. The reaction was cooled to room temperature 5 and diluted with EtOAc (200ml) and water (50ml). The organic layer was separated,dried over MgS04, filtered and solvent evaporated yielding a residue which was purified on silica gel eluting with 85% v/vEtOAc/hexanes yielding product 81 as white solid. (0.7g, 63%). ESMS (MH, 250). 10 Step 2 Preparation of 5-(4-Piperazin-1-yl-phenyl)-pyrimidin-2-ylamine H ,N. o Pd (OAc)2 N DBBP H CS2C03/dioxane/H20 82 A mixture of 5-(4-bromo-phenyl)-pyrimidin-2-ylamine (100mg, 0.401 mmol),palladium acetate (20mg, 0.089mmol), cesium carbonate (200mg, 15 0.62mmol), piperazine(100mg, 1.16mmol) and 2-di-t-butylphosphino)-biphenyl (50mg, 0.167mmol) was stirred in dioxane:water (10ml, v/v 5:1) at reflux temperature for 4 hours. The reaction was cooled, diluted with MeCl2 (100ml) and H20 (50ml). The organic layer was separated, dried (MgS04), filtered and solvent evaporated. The residue was purified by chromatography eluting with 100% EtOAc then with 10% v/v 20 Me0H/Et0Ac/NH40H yielding product 82 as a white solid. (70mg.68%) ESMS (MH, 256). RECIEVED IPONZ 22 AUGUST 2011 -253- Step 3 Preparation of 1 -(2-{4-[4-(2-Amino-pyrimidin-5-yl)-phenyl]-piperazin-1 -yl}-2-oxo-ethyl)-pyrrolidine-3-carboxylic acid [3-(4-fluoro-phenyl)-1 H-indazol-6-yl]-amide 82 + 67 EDCI, HOBT 1 DMF, (C2H5)3N O o 83 Following a procedure similar to that described in Example 98 Step 8, but substituting 82 for 77, the title product 83 was obtained as a white solid (ESMS, MH 620) C34H35NgF02 LCMS (MH 620) Retention time = 2.52 minutes. EXAMPLE 125 10 Step 1 Preparation of 2-(ferf-butyl-dimethyl-silanyloxymethyl)-acrylic acid ethyl ester I EtOOC OH EtOOC O-Si 85 84 To a stirred solution of 2-hydroxymethyl-acrylic acid ethyl ester (260 mg, 2 mmol) and imidazole (163 mg, 2.4 mmol) in dry DMF (5 ml) was added tert-15 butyldimethylsilyl chloride (362 mg, 2.4 mmol). The reaction mixture was stirred overnight and diluted with ether, washed with water three times and dried over MgS04. Solvent was removed under reduced pressure to provide a crude product that was purified by column chromatography using a solution of ethyl acetate in hexanes (1:6) to obtain the title product (463 mg, 95%). 20 RECIEVED IPONZ 22 AUGUST 2011 -254- Step 2 10 15 Preparation of 1 -benzyl-3-(ferf-butyl-dimethyl-silanyloxymethyl)-pyrrolidine-3-carboxylic acid ethyl ester To a cold solution of 2-(terf-butyl-dimethyl-silanyloxymethyl)-acrylic acid ethyl ester (463 mg, 1.89 mmol) and A/-(methoxymethyl)-A/-(trimethylsilylmethyl)benzyl-amine (540 j_lI, 2.11 mmol) in dichloromethane (3 ml) was added at 0 °C trifluoroacetic acid (26 j_lI, 0.34 mmol). The resulting solution was warmed to room temperature in two hours. The crude product was purified by column chromatography on silica get eluting with a solution of ethyl acetate in hexanes (1:10, 1:5) to give the title compound (490 mg, 69%). Step 3 Preparation of 3-(fert-butyl-dimethyl-silanyloxymethyl)-pyrrolidine-3-carboxylic acid ethyl ester A mixture of 1-benzyl-3-(ferf-butyl-dimethyl-silanyloxymethyl)-pyrrolidine-3-carboxylic acid ethyl ester (690 mg, 1.83 mmol), ammonium formate (461 mg, 7.31 mmol), 10% Pd/C (100 mg) in methanol (10 ml) and water (1 ml) was refluxed overnight. The mixture was filtered through celite, washed with ethyl acetate. The combined filtrate was concentrated and the residue was taken into ethyl acetate, washed with brine and dried over MgS04. Evaporation of solvent provided the title compound as oil (444 mg, 84%). Si'^N'^OMe 86 Ph + RECIEVED IPONZ 22 AUGUST 2011 -255- Step 4 Synthesis of 1-ferf-butoxycarbonylmethyl-3-(ferf-butyl-dimethyl-silanyloxymethyl)-pyrrolidine-3-carboxylic acid ethyl ester A EtOOC \ ,0 88 ^Si NH \ \ ■ EtOOC 5 To a stirred mixture of 3-(fe/t-butyi-dimethyi-silanyioxymethyl)-pyrrolidine-3- carboxylic acid ethyl ester (444 mg, 1.54 mmol), triethylamine (214 |ulI, 1.54 mmol) and cesium carbonate (251 mg, 0.77 mmol) in acetonitrile (5 ml) was added tert-butyl bromoacetate (351 |ulI, 2.38 mmol) slowly. The mixture was stirred for 1 hour, filtered and concentrated. The residue was diluted with ethyl acetate, washed with water and 10 dried over MgS04. Solvent was removed under reduced pressure to give a crude product that was purified by column chromatography on silica gel. Elution with a solution of ethyl acetate in hexanes (1:4) provided 580 mg (94%) of the title compound. 15 Step 5 Preparation of 1 -ferf-butoxycarbonylmethyl-3-hydroxymethyl-pyrrolidine-3-carboxylic acid ethyl ester 20 butoxycarbonylmethyi-3-(te/t-butyl-dimethyl-silanyloxymethyl)-pyrrolidine-3-carboxylic acid ethyl ester (726 mg, 1.8 mmol). The reaction solution was stirred for half hour and purified by column chromatography using solution of ethyl acetate in hexanes (1:1), then ethyl acetate to provide the title product (350 mg, 68%). Tetrabutylammonium fluoride (1.8 ml, 1M in THF) was added to 1 -tert- RECIEVED IPONZ 22 AUGUST 2011 10 -256- Step 6 Preparation of methyl 2-(methoxymethyl) aery I ate MeOOC MeOOC MeONa r-h Br—' MeO 91 92 To a stirred mixture of methyl 2-(bromomethyl)acrylate (239 jil, 2 mmol) in petroleum ether (3 ml) was added potassium carbonate (276 mg, 2 mmol), followed by sodium methoxide (119 mg, 2.2 mmol) and methanol (450 jil). The resulting mixture was stirred overnight, filtered, concentrated to a residue that was purified by column chromatography eluting with 10% ether in hexanes to provide the title compound (150 mg, 58%). (Reference: J. Med.Chem.; 42; 15; 1999; 2760-2773.) Step 7 Preparation of 1-benzyl-3-methoxymethyl-pyrrolidine-3-carboxylic acid methyl ester \ mQnnr TFA MeOOC. / ~i "S| L °MC + w /VN^,Ph Ph MeO OMe 93 92 94 15 To a stirred solution of methyl 2-(methoxymethyl) acrylate (176 mg, 1.35 mmol) and A/-(methoxymethyl)-A/-(trimethylsilylmethyl)benzylamine (416 jil, 1.63 mmol) in dichloromethane (2 ml) was added at 0 °C trifluoroacetic acid (21 jil, 0.27 mmol). The resulting solution was warmed to room temperature and stirred overnight. The crude product was purified by column chromatography on silica, eluted with a solution of 20 ethyl acetate in hexanes (1:3), then 5% methanol in ethyl acetate to give the title compound (293 mg, 82%). RECIEVED IPONZ 22 AUGUST 2011 -257- Step 8 Preparation of 3-methoxymethyl-pyrrolidine-3-carboxylic acid methyl ester MeOOC HCOONH4 MeOOC NH OMe Pd/C OMe 95 94 A mixture of 1-benzyl-3-methoxymethy!-pyrrolidine-3-carboxylic acid methyl 5 ester (373 mg, 1.42 mmol), ammonium formate (358 mg, 5.68 mmol), 10% Pd/C (100 mg) and methanol (6 ml) was refluxed overnight. The mixture was filtered through Celite, washed with ethyl acetate. The combined filtrate was concentrated and the residue was taken into ethyl acetate, washed with small amount of water. Aqueous layer was isolated, extracted with dichloromethane three times. The dichloromethane 10 extracts were combined with previous ethyl acetate extracts and dried over MgS04. Evaporation of solvents provided the title compound as oil (140 mg, 57%). Preparation of 1 -tert-butoxycarbonylmethyl-3-methoxymethyl-pyrrolidine-3 15 carboxylic acid methyl ester To a stirred mixture of 3-methoxymethyl-pyrrolidine-3-carboxylic acid methyl ester (140 mg, 0.81 mmol), triethylamine (112 jnl, 0.82 mmol) and cesium carbonate (263 mg, 0.81 mmol) in acetonitrile (2 ml) was added terf-butyl bromoacetate (119 jnl, 20 0.81 mmol) slowly. The mixture was stirred for 15 minutes, filtered and concentrated. The residue was purified by column chromatography on silica gel. Elution with a solution of ethyl acetate and hexanes (1:2) provided 118 mg (51%) of the title compound. Step 9 OMe 95 OMe 96 RECIEVED IPONZ 22 AUGUST 2011 -258- 10 Step 10 Preparation of 1-carboxymethyl-3-methoxymethyl-pyrrolidine-3-carboxylic acid methyl ester MeOOC./—| O TFA MeOOC./ | O <V-N^AoX ► 0-N^OH OMe OMe 96 97 The 1 -ferf-butoxycarbonylmethyl-3-methoxymethyl-pyrrolidine-3-carboxylic acid methyl ester (118 mg) was treated with trifluoroacetic acid (2 ml), stirred for 20 minutes and evaporated to a residue that was exchanged with hydrochloric acid (1 ml, 4N) and lyophilized overnight to a gummy title product. Step 11 Preparation of 3-methoxymethyl-1 -{2-oxo-2-[4-(4-pyrimidin-2-yl-phenyl)-piperazin-1-yl]-ethyl}-pyrrolidine-3-carboxylic acid methyl ester MeOOC^ O OMe 97 + 10 ► 98 15 To a solution of 1-carboxymethyl-3-methoxymethyl-pyrrolidine-3-carboxylic acid methyl ester (compound 97) (0.21 mmol), 2-(4-piperazin-1-yl-phenyl)-pyrimidine (compound 10, see Example 1 Step 7) (0.21 mmol), 0-(7-azabenzotriazol-1-yl-)-A/,A/,A/',A/-tetramethyluronium hexafluorophosphate (HATU) (78 mg, 0.21 mmol) in dry 20 DMF (2 ml) was added N, A/-diisopropylethylamine (108 jxl, 0.62 mmol). The reaction mixture was stirred for 4 hours, and evaporated to a residue that was partitioned in ethyl acetate and saturated sodium carbonate. Organic layer was isolated, washed with water, brine and dried over magnesium sulfate. Evaporation of solvent provided a crude product which was chromatographed with 5% methanol in dichloromethane to 25 furnish the title compound (97 mg). RECIEVED IPONZ 22 AUGUST 2011 -259 10 15 20 Step 12 Preparation of 3-methoxymethyl-1 -{2-oxo-2-[4-(4-pyrimidin-2-yl-phenyl)-piperazin-1 -yl]-ethyl}-pyrrolidine-3-carboxylic acid MeOOC OMe l^flj 98 HOOC OMe 99 The 1-carboxymethyl-3-methoxymethyl-pyrrolidirie-3-carboxylic acid methyl ester (97 mg, 0.21 mmol) was saponified with lithium hydroxide monohydrate (27 mg, 0.64 mmol) in tetrahydronfuran and water (2:1, 3 ml) for 2 hours. The reaction mixture was acidified with 4 N HCI and lyophilized overnight to provide the title compound which was directly used in the next step synthesis. Step 13 Preparation of 3-methoxymethyl-1 -{2-oxo-2-[4-(4-pyrimidin-2-yl-phenyl)-piperazin-1 -yl]-ethyl}-pyrrolidine-3-carboxylic acid [3-(4-fluoro-phenyl)-1 H-indazol-5-yl]-amide 99 + 65 The 3-methoxymethyl-1 -{2-oxo-2-[4-(4-pyrimidin-2-yl-phenyl)-piperazin-1 -yl]-ethyl}-pyrrolidine-3-carboxylic acid (0.049 mmol), 1-hydroxybenztriazole (7 mg, 0.052 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) (10 mg, 0.052 mmol) were dissolved in dry DMF (1 ml). 3-(4-Fluoro-phenyl)-1/-/-indazol-5-ylamine (12 mg, 0.053 mmol) was added and the reaction mixture was stirred overnight and directly subjected to purification by reversed phase HPLC to obtain 9.15 mg of the title product. Mass Spec.: 649, Retention Time: 3.93 minutes. RECIEVED IPONZ 22 AUGUST 2011 -260-EXAMPLE 126 Step 1 Preparation of 2-fluoromethyl-acrylic acid ethyl ester EtOOC DAST EtOOC HO 84 101 5 To a solution of (diethylamino)sulfur trifluoride (DAST) (363 jllI, 2.76 mmol) in dichloromethane (1 ml) was slowly added at -78 C a solution of 2-hydroxylmethyl acrylic acid ethyl ester (300 mg, 2.31 mmol) in dichloromethane (3 ml). The reaction mixture was allowed to warm to room temperature, re-chilled to -78C and additional DAST (100 jllI, 0.76 mmol) was added to ensure complete reaction. The reaction 10 mixture was let to warm to room temperature and quenched with saturated sodium carbonate. Organic layer was isolated, washed with water, brine and dried (MgS04). The dichloromethane solution was directly passed through a short silica gel pad, eluted with dichloromethane and the product fractions were collected. The combined fractions (ca. 12 ml) will be directly used in the next step synthesis without further 15 concentration. Step 2 Preparation of 1-benzyl-3-fluoromethyl-pyrrolidine-3-carboxylic acid ethyl ester 20 A/-(methoxymethyl)-A/-(trimethylsilylmethyl)benzylamine (548 jllI, 2.14 mmol) was dissolved in the dichloromethane solution of the 2-fluoromethyl-acrylic acid ethyl ester from the previous reaction and chilled to 0 C. A solution of trifluoroacetic acid (67 |il, 0.87 mmol) in dichloromethane (0.5 ml) was added slowly. The reaction mixture was allowed to warm to room temperature in two hours and directly 25 chromatographed on silica gel. Elution with solutions of ethyl acetate in hexanes (1:5, 1:4, 1:3) obtained the title product (143 mg) as oil. RECIEVED IPONZ 22 AUGUST 2011 -261 - EXAMPLE 127 Preparation of 3-Allyl-pyrrolidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester )^OjBoc o 2 Pyrrolidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester 2 (see Example 1, Step 1) (4.58 g, 20 mmol) was dissolved in THF (100 mL) and cooled down to -78°C in a dry ice-acetone bath. LDA (12 mL, 2.0 M, 24 mmol) was then added dropwise. The mixture was stirred at -78°C for 1 hr. Allyl bromide (5.3 mL, 61 mmol) was added in neat. The reaction was allowed to warm to rt naturally and stirred for 24 hrs. It was then quenched with sat. NH4CI solution, extracted with ethyl acetate 2X150 mL. The organic layer was washed with brine, dried (MgS04) and concentrated. The crude was purified on silica gel column using 4:1 hexanes/ethyl acetate to get the title compound (3.6g) as a yellow oil. MS (292, MNa). EXAMPLE 128 Step 1 Preparation of (S,S)-5-[4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-2,5-diaza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester 105 A mixture of (S,S)-5-(4-Bromo-phenyl)-2,5-diaza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (4.Og, 11.3 mmol), Bis(pinacolato)diboron (4.0g, 15.7 mmol), KOAc (3.2g) and CI2Pd(dppf)CH2CI2 (800 mg) in 40 mL dioxane was evacuated and recharged with N2 several times. The reaction mixture was then heated to 85 °C overnight. After cooling down to rt, 150 mL ethyl acetate and 30 mL RECIEVED IPONZ 22 AUGUST 2011 -262- water was added. The mixture was filtered through a pad of Celite and washed with additional ethyl acetate. The separated organic layer was dried (MgS04) and concentrated. The crude was purified on silica gel column eluting with 30% to 50 % ethyl acetate/hexanes to yield the title compound as a white solid (3.3 g). MS (401, MH) Step 2 Preparation of (S,S)-5-[4-(5-Fluoro-pyrimidin-2-yl)-phenyl]-2,5-diaza-bicyclo[2.2.1]-heptane-2-carboxylic acid tert-butyl ester A mixed DMF/H20 (5 mL/5 mL) solution of (S,S)- 5-[4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-2,5-diaza-bicyclo[2.2.1] heptane-2-carboxylic acid tert-butyl ester (800 mg, 2mmol), 2-chloro-5-fluoro-pyrimidine (340 mg, 2.6 mmol), K2CO3 (552 mg, 4 mmol) and Cl2Pd(dppf)CH2Cl2 (160 mg) was evacuated and recharged with N2 several times. The reaction was heated at 70 °C over 18 hrs. After cooling down to rt, 40 mL ethyl acetate and 10 mL water was added. The mixture was filtered through a pad of Celite and washed with additional ethyl acetate. The separated organic layer was dried (MgS04) and concentrated. The crude was purified on silica gel column eluting with 50 % ethyl acetate/hexanes to yield the title compound (420 mg) as a light yellow solid. Boc F 106 105 RECIEVED IPONZ 22 AUGUST 2011 -263- In a similar mariner, 106a: Boc u 106a was prepared by substituting 2-chloropyrimidine for2-chloro-5-fluoro-pyrimidine. EXAMPLE 129 Preparation of 4-[4-(5-Fluoro-pyrimidin-2-yl)-phenyl]-piperazine-1 -carboxylic acid tert-butyl ester 4-[4-(5-Fluoro-pyrimidin-2-yl)-phenyl]-piperazine-1 -carboxylic acid tert-butyl 10 ester was prepared similarly as the above substituting (S,S)-5-[4-(4,4,5,5-tetra- methyl[1,3,2]dioxaborolan-2-yl)-phenyl]-2,5-diaza-bicyclo[2.2.1 ] heptane-2-carboxylic acid tert-butyl ester with 4-[4-(tert-Butoxycarbony)piperazin-1-yl]phenylboronic acid (C. Chen et. al. J. Org. Chem. 2003, 68, 2633). 15 RECIEVED IPONZ 22 AUGUST 2011 -264-EXAMPLE 130 Preparation of (S,S)-5-(5-Vinyl-pyrimidin-2-yl)-2,5-diaza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester Boc Boc 109 110 5 (S,S)-5-(5-Bromo-pyrimidin-2-yl)-2,5-diaza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (177 mg, 0.5 mmol), tributyl vinyl tin (634 mg, 2 mmol) and Cl2Pd(dppf)CH2Cl2 (60 mg) was mixed in DMF (3 mL). The mixture was heated at 90 °C over 3 days. The cooled down reaction was participate between ethyl acetate (50 mL) and H20 (10 mL). The organic layer was washed with H20 (10 mL), brine (10 10 mL), dried (MgS04) and filtered. The conc. filtrate was purified on silica gel column eluting with 33% to 50% ethyl acetate/hexanes to yield the title compound as a white solid (54 mg). MS (303, MH). EXAMPLE 131 15 Preparation of 1 H-Pyrazolo[3,4-b]pyridin-5-ylamine 5-Nitro-1 H-pyrazolo[3,4-b]pyridine (prepared according to the procedure in Can. J. Chem. 1988, 66(3), 420) (133 mg, 0.81 mmol) was mixed with SnCI2 (1.0g) in EtOH/CH3Ph (4 mL/2mL) and heated at 70 °C for 3 hrs. The reaction was cooled to rt 20 and concentrated to dryness. The residue was participated between 1.0 N NaOH (10 mL) and ethyl acetate (50 mL). The organic layer was washed with brine once, dried (MgS04) and filtered. The filtrate was concentrated and the resulting crude was purified by prep. TLC using 10:2 CH2CI2/Methanol(2 N NH3). The title compound (15.0 mg) was isolated as a yellow solid. 25 RECIEVED IPONZ 22 AUGUST 2011 -265-EXAMPLE 132 Preparation of 4-Hydroxy-4-thiazol-2-yl-piperidine-1-carboxylic acid tert-butyl ester (f Br (f YlBoc N N HO N ' 113 114 5 2-Bromo-thiazole (0.27 mL, 2.99 mmol) was dissolved in Et20 (8 mL) and cooled down to - 78 °C. BuLi (1.3 mL, 2.5 M) was added dropwise. The resulting yellow solution was stirred at -78 °C for 45 min. 4-Oxo-piperidine-1-carboxylic acid tert-butyl ester (720 mg, 3.61 mmol) in Et20 (5 mL) was then added dropwise. The reaction temperature rose to rt naturally overnight. H20 (10 mL) was added to 10 quench the reaction and extracted with ethyl acetate. The combined organic layer was dried (MgS04), filtered and concentrated. The residue was purified on silica gel column eluting with 33% to 50% ethyl acetate/hexanes to give 4-Hydroxy-4-thiazol-2-yl-piperidine-1-carboxylic acid tert-butyl ester (800 mg) as a colorless oil. 15 EXAMPLE 133 Step 1 Preparation of 4-Thiazol-2-yl-piperazine-1-carboxylic acid tert-butyl ester / \ /—\ HN N—& |l ► Boc-N N—(\ jl \ / s N / N 115 116 To a solution of 1-thiazol-2-yl-piperazine (2 g, 12 mmol), triethylamine (2.4 g, 20 24 mmol) and DMAP (150 mg, 1.2 mmol) in acetonitrile (15 ml) was added di-tert-butyl dicarbonate. The resulted reaction mixture was stirred at RT for 3 hours. Then water (20 mL) was added and the formed slurry was stirred for 30 min. The formed product was collected by filtration and washed with water. After dry in air, 2.8 g product was obtained (90 % yield) 25 RECIEVED IPONZ 22 AUGUST 2011 -266- Step 2 Preparation of 4-(5-Bromo-thiazol-2-yl)-piperazine-1 -carboxylic acid tert-butyl ester 5 To a mixture containing 4-thiazol-2-yl-piperazine-1-carboxylic acid tert-butyl ester (0.5 g, 1.9 mmol) and cesium carbonate (0.62 mmol) in chloroform (5 mL) at 0 °C, bromine (110 mL) was added through a syringe. After the addition, the reaction mixture was stirred at room temperature for 1 hour. Water was added and the organic layer was collected and dried over sodium sulfate. After removal of solvent, 0.6 g of 10 product was obtained (95% yield). EXAMPLE 134 Preparation of 5-Thiazol-2-yl-2, 5-diaza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (S) 15 118 119 A mixture of 2-bromothiazole (200mg,1.22mmol), palladium acetate (15 mg, 0.06 mmol), sodium terf-butoxide ( 217 mg, 2.26 mmol), (S, S) 2,5-diaza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (280mg, 1.4 mmol) and 2-Di-t-butylphosphino)-biphenyl (37 mg, 0.118mmol) was stirred in dioxane (10ml) at 80 °C 20 for overnight. The reaction was cooled, diluted with ethyl acetate (40 ml) and H20 (50ml).The organic layer was separated, dried (Na2S04), filtered and solvent evaporated. The residue was purified by chromatography eluting with 5% MeOH/DCM yielding product as a white solid. (180 mg, 52% yield) Boc-N^VlH -► Boc i 25 RECIEVED IPONZ 22 AUGUST 2011 -267-EXAMPLE135 Step 1 Preparation of 4-(5-Pyrimidin-2-yl-thiazol-2-yl)-piperazine-1-carboxylic acid tert-butyl ester / \ Boc-N N—JJ ► Boc-N \ / N 117 5 N^ A round bottom flask containing 4-(5-bromo-thiazol-2-yl)-piperazine-1-carboxylic acid tert-butyl ester (100 mg, 0.29 mmol), 2-tributylstannanyl-pyrimidine (130 mg, 0.36 mmol), cesium fluoride (85 mg, 0.56 mmol) and palladium di-tert-butylphosphine was degassed three times with Ar. Dioxane was added and the 10 formed reaction mixture was stirred at 90 °C overnight under Ar. Then the reaction mixture was filter through celite and the solvent was removed under vacuum and crude product was used directly in the next step. Step 2 15 Preparation of 2-(2-Piperazin-1 -yl-thiazol-5-yl)-pyrimidine /—\ N--i Boc-N N—(f |1 ► HN To the crude product obtained in the previous step, was added 90% TFA (1 mL) and the reaction mixture was stirred at ambient temperature for 1 hour. The excess TFA was removed under vacuum and the residue was purified using prep-20 HPLC to give desired product (45 mg, 44 % yield for two steps) as TFA salt. RECIEVED IPONZ 22 AUGUST 2011 -268- Step 3 Preparation of 5-[(1 -{2-Oxo-2-[4-(5-pyrimidin-2-yl-thiazol-2-yl)-piperazin-1 -yl]-ethyl}-pyrrolidine-3-carbonyl)-amino]-1H-indazole-3-carboxylic acid methylamide To a solution of [3-(3-methylcarbamoyl-1 H-indazol-5-ylcarbamoyl)-pyrrolidin-1-yl]-acetic acid (15 mg, 0.043 mmol, prepared by a procedure similar to that of Example 98 using the indazole of Example 85 instead of indazole 65) and HOBt (7 10 mg, 0.052 mmol) in DMF (0.5 mL) at 0 °C, EDCI (10 mg, 0.052 mmol) was added and the resulted reaction mixture was stirred at this temperature for 0.5 hour. To this solution was added 2-(2-Piperazin-1-yl-thiazol-5-yl)-pyrimidine (18 mg, 0.052 mmol) made from previous step, followed by DIEA (7 |iL). The reaction was stirred at 0 °C for 1 hour and was gradually warm up to room temperature and was continuously 15 stirred for overnight. Ethyl acetate (5 mL) was then added, followed by water (10 mL). The organic layer was collected, dry over sodium sulfate, evaporate of solvent and residue was purified using prep-HPLC. To the solution obtained from HPCL, HCI (1N, 2 mL) was added and the solution was brought to dryness under vacuum. The formed residue was then dissolved in acetonitrile/water (3:1) and was lyophilized to 20 give desired product (10 mg, 38 % yield) as hydrochloride salt. EXAMPLE 136 Step 1 Preparation of 4-(4-Bromo-phenyl)-piperidine-1 -carboxylic acid tert-butyl ester HN00Br —Boc-O^G^Br 25 122 123 To a solution of 4-(4-bromo-phenyl)-piperidine (2.8 g, 12 mmol), triethylamine (2.4 g, 24 mmol) and DMAP (150 mg, 1.2 mmol) in acetonitrile (15 ml) was added di- RECIEVED IPONZ 22 AUGUST 2011 -269- tert-butyl dicarbonate. The resulted reaction mixture was stirred at RT for 3 hours. Then water (20 mL) was added and the formed slurry was stirred for 30 min. The formed product was collected by filtration and washed with water. After dry in air, 3.8 g product was obtained (95 % yield). Step 2 Preparation of 4-(4-Pyrimidin-2-yl-phenyl)-piperidine-1-carboxylic acid tert-butyl ester / V /=v N=\ 123 124 10 A mixture containing 4-(4-bromo-phenyl)-piperidine-1 -carboxylic acid tert-butyl ester (100 mg, 0.29 mmol), 2-tributylstannanyl-pyrimidine (130 mg, 0.36 mmol), cesium fluoride (85 mg, 0.56 mmol) and palladium di-tert-butylphosphine was degassed three times with Ar. Dioxane was added and the formed, reaction mixture was stirred at 90 °C overnight under Ar. Then the reaction mixture was filter through 15 celite and the solvent was removed under vacuum and crude product was used directly in the next step. Step 3 Preparation of 2-(4-Piperidin-4-yl-phenyl)-pyrimidine *k-v)_0_0 —hO~C}~C} 20 124 125 To the crude product obtained in the previous step, was added 90% TFA (1 mL) and the reaction mixture was stirred at ambient temperature for 1 hour. The excess TFA was removed under vacuum and the residue was purified using prep-HPLC to give desired product (38 mg, 37 % yield for two steps) as TFA salt. 25 RECIEVED IPONZ 22 AUGUST 2011 -270-EXAMPLE 137 Step 1 Preparation of 4-Thiazol-2-yl-3, 6-dihydro-2H-pyridine-1 -carboxylic acid tert-butyl ester 126 127 To a mixture of (N-tert-butoxycarbonyl)-l ,2,3,6-tetrahydropryidine -2-boronic acid pinacol ester (100 mg, 0.32 mmol), 2-bromothiazole (64 mg, 0.39 mmol), PdCI2(dppf) (24 mg, 0.03 mmol) and potassium phosphate (213 mg, 1 mmol) was degassed three times with Ar, was added dixoane. The formed reaction mixture was then heated at 80 °C overnight under Ar. After the reaction was complete, the mixture was filter through celite and was chromatographed on a silica column (10% ethyl acetate/DCM) to obtain desired product (30 mg, 35% yield). Step 2 Preparation of 4-Thiazol-2-yl-1, 2, 3, 6-tetrahydro-pyridine 127 128 To the product obtained in the previous step, was added 90% TFA (1 mL) and the reaction mixture was stirred at ambient temperature for 1 hour. The excess TFA was removed under vacuum and the residue was purified using prep-HPLC to give desired product (15 mg, 50 % yield) as TFA salt. RECIEVED IPONZ 22 AUGUST 2011 -271 - EXAMPLE 138 Step 1 Preparation of 4-(methoxy-methyl-carbamoyl)-piperidine-1 -carboxylic acid tert-5 butyl ester /V,0-dimethylhydroxylamine hydrochloride (851 mg, 8.72 mmols) was suspended in dichloromethane (6 ml) and cooled to 0 C. N, /V-diisopropylethylamine (1.66 ml, 9.53 mmols) was added and the mixture was stirred at 0 C until a clear 10 solution was obtained. The resulting solution was kept at 0 C for further use. Boc-isonipecotic acid (2 g, 8.72 mmol), 1-hydroxybenzotriazole (1.2 g, 8.88 mmols) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) (1.83 g, 9.58 mmols) were dissolved in DMF (15 ml) and cooled to 0 C. The solution of A/,0-dimethylhydroxylamine in dichloromethane was added with stirring, and the resulting 15 reaction mixture was allowed to stir overnight at room temperature. DMF was removed under reduced pressure and residue was partitioned between ethyl acetate and 10% citric acid. Organic layer was isolated, washed with water, saturated NaHC03, water and brine and dried over MgS04. Solvent was removed under reduced pressure and the residue was purified on silica gel eluting with ethyl acetate 20 in hexanes (2:1) to provide the title compound (1.88 g, 79%). LCMS m/e (295, M + Na). Step 2 Preparation of 4-formyl-piperidine-1-carboxylic acid ferf-butyl ester OMe OMe BOC 129 BOC 130 25 BOC 130 BOC 131 RECIEVED IPONZ 22 AUGUST 2011 -272- To a mixture of lithium aluminum hydride (1M THF solution, 4.4 ml) in ether (4 ml) was added dropwise at - 60 C 4-(methoxy-methyl-carbamoyl)-piperidine-1-carboxylic acid tert-butyl ester (1 g, 3.67 mmols) in ether (6 ml). The reaction mixture was allowed to warm to 0-5 C and then re-cooled to -60 C. Celite was added and reaction was quenched with a solution of KHS04 (1 g) in water (3 ml), filtered through Celite. The filtrate was washed with cold 1N HCI, saturated NaHC03, brine and dried (MgS04) and concentrated. The residue was purified by column chromatography on silica gel eluting with ethyl acetate in hexanes (1:1) to provide title compound (656 mg, 84%). {Org. Prep. Proced. Int., 2000, 32, 96.) To a solution of tosyl chloride (4 g, 21 mmols) in acetone (60 ml) was added at 0-5 C a solution of sodium azide (1.37 g, 21 mmols) and the resulting solution was stirred at that temperature for 2 hours. Acetone was removed and the aqueous mixture was extracted with ether three times. The combined extracts were dried over MgS04. Evaporation of solvents provided tosyl azide (4g, 97%). {Eur. J. Org. Chem. 2003, 821-832.) Step 2 Preparation of (1-diazo-2-oxo-propyl)-phosphonic acid dimethyl ester N3 0=s=0 0=s=0 132 133 0=s=0 n2 134 133 RECIEVED IPONZ 22 AUGUST 2011 -273- To a suspension of NaH (60% in mineral oil, 0.83 g, 20.8 mmols) in THF (50 ml) was added dropwise at 0 C (2-oxo-propyl)-phosphonic acid dimethyl ester (3.1 g, 18.7 mmols) in THF (50 ml), and the solution was stirred at 0 C for one hour. Tosyl azide (4g, 20 mmols) was added in one portion, stirred at 0 C for 10 minutes, filtered 5 through Celite and concentrated. The residue was purified by column chromatography on silica gel using ethyl acetate to yield the title compound (2.9 g, 81%) as oil. {Eur. J. Org. Chem. 2003, 821-832.) Step 3 10 Preparation of 4-ethynyl-piperidine-1 -carboxylic acid ferf-butyl ester At 0 C, to a stirred mixture of 4-formyl-piperidine-1 -carboxylic acid tert-butyl ester (358 mg, 1.68 mmols) and potassium carbonate (464 mg, 3.36 mmols) in methanol (16 ml) was added dropwise a solution of (1-diazo-2-oxo-propyl)-15 phosphonic acid dimethyl ester (323 mg, 1.68 mmols) in methanol (2 ml). The resulting mixture was stirred at room temperature overnight, filtered and concentrated. The residue was chromatographed on silica gel using a solution of ethyl acetate in hexanes (1:5) to provide the title compound (308 mg, 88%) as colorless crystals. LCMS m/e (154, M - f-Bu + 2H). (J. Am. Chem. Soc. 2003, 125, 3714.) BOC 131 N2 134 BOC 135 20 Step 4 Preparation of 4-phenylethynyl-piperidine-1-carboxylic acid ferf-butyl ester BOC 135 RECIEVED IPONZ 22 AUGUST 2011 -274- lodobenzene (135 jllI, 1.2 mmols), 4-ethynyl-piperidine-1 -carboxylic acid tert-butyl ester (209 mg, 1 mmols) and triethylamine (167 jllI, 1.2 mmols) were dissolved in acetonitrile (6 ml). Dichlorobis(triphenylphosphine)palladium(ll) (35 mg, 0.05 mmols) and Cul (10 mg, 0.05 mmols) were added, and reaction mixture was stirred at room 5 temperature overnight and continued to stir at 50 C for two more hours before partitioning between ethyl acetate and water. Organic layer was isolated, washed with 1 N HCI, brine and dried (MgS04). Solvents were removed and residue was purified by column chromatography on silica gel using solutions of ethyl acetate in hexanes (1:4; 1:2) to yield the title compound (74 mg). LCMS m/e (230, M - f-Bu + 10 2H) Step 5 Preparation of 4-phenylethynyl-piperidine bocnCk=-0 —~ n0~=~0 -136 137 15 4-Phenylethynyl-piperidine-1-carboxylic acid ferf-butyl ester was treated with TFA for 10 minutes and concentrated, lyophilized to provide the title product. EXAMPLE 140 Step 1 20 Preparation of 4-pyrimidin-2-ylethynyl-piperidine-1 -carboxylic acid ferf- butyl ester 135 To a suspension of 2-bromopyrimidine (175 mg, 1.1 mmols), dichlorobis(triphenylphosphine)palladium(ll) (35 mg, 0.05 mmols) and Cul (10 mg, 25 0.05 mmols) was added a solution of 4-ethynyl-piperidine-1-carboxylic acid ferf-butyl ester (209 mg, 1 mmol). The mixture was stirred overnight, filtered through Celite, concentrated. The residue was partitioned between ethyl acetate and water, organic layer was isolated, dried (MgS04), and concentrated. The residue was RECIEVED IPONZ 22 AUGUST 2011 -275- chromatographed on silica gel eluting with ethyl acetate in hexanes (1:1) to give un-reacted 2-bromopyrimidine (130 mg), then the title compound (23 mg). LCMS m/e (288, M + H). Step 2 Preparation of 2-piperidin-4-ylethynyl-pyrimidine 4-Pyrimidin-2-ylethynyl-piperidine-1-carboxylic acid ferf-butyl ester was treated with TFA for 10 minutes and concentrated, lyophilized to provide the title product. EXAMPLE 141 Preparation of 5-({1 -[2-oxo-2-(4-phenylethynyl-piperidin-1 -yl)-ethyl]-pyrrolidine-3-carbonyl}-amino)-1H-indazole-3-carboxylic acid methylamide ch3 ch3 A solution of [3-(3-methylcarbamoyl-1 H-indazol-5-ylcarbamoyl)-pyrrolidin-1-yl]-aceticacid (0.13 mmols), 4-phenylethynyl-piperidine (0.13 mmols), 1-hydroxybenztriazole (18 mg, 0.13 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) (27 mg, 0.14 mmol) and DIEA (45 j_il, 0.26 mmols) was stirred overnight and directly subjected to purification by reversed phase HPLC to obtain 16 mg of the title product. EXAMPLE 142 Preparation of 5-({1 -[2-oxo-2-(4-pyrimidin-2-ylethynyl-piperidin-1 -yl)-ethyl]-pyrrolidine-3-carbonyl}-amino)-1 H-indazole-3-carboxylic acid methylamide RECIEVED IPONZ 22 AUGUST 2011 -276- Following a procedure similar to that of Example 141, but using 2-piperidin-4-ylethynyl-pyrimidine instead of 4-phenylethynyl-piperidine the title compound was prepared. EXAMPLES 143 TO 151 Following a procedure similar to Example 135, Step 3, but using the appropriately substituted piperazine, and the suitably substituted indazole, and the appropriate amine for MeNH2 in Example 87, the compounds in Table 9 can be prepared. TABLE 9 Example COMPOUND 143 !1 OY- x~nh2 r o ch3 144 ) if" /=0 ch3 n \ ch3 RECIEVED IPONZ 22 AUGUST 2011 -277 - 145 y O^rx ^ h3c-n^° \ ch3 146 j~\-} QJL X rS n^° \ ch3 147 X °YA /*° °Ha Br 148 & >=Z o o 149 ryKUp Y^i x0 1 1 RECIEVED IPONZ 22 AUGUST 2011 -278- 150 *PKU0 n <! i 0 151 />RlJ r\J O \ oJ^T V \ ch, nh2 3 EXAMPLES 152 TO 155 Following a procedure similar to that of Example 85, but using the appropriately substituted piperazine derivative, as prepared according to the procedures in 5 Examples 128-134, the compounds in Table 10 were prepared. TABLE 10 Example COMPOUND 152 XY" W=d V-n o nch3 153 j~\-} ^ ¥ iV ch3 RECIEVED IPONZ 22 AUGUST 2011 -279- 154 n n^^ch3 \ 3 ch3 155 rQh \\ /) Wo n \ ch3 EXAMPLE 156 Following a procedure similar to that of Example 125, Using compound 90 from Example 125 Step 5 in place of compound 96 in Step 10, and using 4-piperazin-1-yl-thiazolyl in place of 2-(4-piperazin-1-yl-phenyl)-pyrimidine in Step 11, the compound in Table 11 was prepared. Table 11 Example Compound Mass Spec Retention time (minutes) 156 9 H ~ "-"J} F 564 2.68 EXAMPLES 157 and 158 Following a procedure similar to that of Example 125, but using the appropriate pyrrolidene and substituted piperazine, as in Example 128, the compounds in Table 12 can be prepared. In Table 12 "Ex" represents "Example". RECIEVED IPONZ 22 AUGUST 2011 -280- Table 12 is Comoound Mass Spec Retention time (minutes) 157 9 F 649 3.74 158 9 ™ ^ 647 3.56 5 EXAMPLES 159 TO 164 Following procedures similar to those described herein, for example, Examples 98, 133 and 135, the compounds in Table 13 were prepared. In Table 13 "Ex" represents "Example". 10 TABLE 13 EX MS Retention Structure (ESMS. time MH) (min.) RECIEVED IPONZ 22 AUGUST 2011 -281 - 159 % nNJk^ ^ 1 L/nV\ ry» Ti \—n N y_, xZ? o (substitute^~^-B(OH)2 for F—^~^~B(OH)2 in Ex. 98 and see Ex. 135) 594 3.25 160 rf>:> co^ X Ovs 0 ^ (see Ex. 133) 516 2.65 161 OJU, Q « f (see Ex. 98 and Ex. 133) 534 2.8 162 i PKUU f \ f (substitute F—^^-B(OH)2 for F—^^-B(OH)2 in Ex. 98 and see Ex. 133) 552 2.95 RECIEVED IPONZ 22 AUGUST 2011 -282- 163 /t~\— n /—1 9 ) <Xx0 N55/ 0 1 1 0 546 3.02 (substitute 0—B(QH)2 for F—B(OH)2 CH3 ~~ ~~ in Ex. 98 and see Ex. 133) 164 idP>OJU nv 0 i i f\ n=/ 518 1.93 (substitute (HO)2B—^ N) for F—B(OH)2 in Ex. 98 and see Ex. 133) Step 1 Preparation of 3-methyl-1-thiazol-2-yl-piperazine H i .N. a\\ I H Br p'tBu \bu + Pd(OAc)2 CS2CO3 dioxane water HN RECIEVED IPONZ 22 AUGUST 2011 -283- A mixture of 2(R)-methyl piperazine (300 mg, 3 mmol), 2-bromo thiazole (0.27 ml, 3 mmol), (2-biphenylyldi-tert-butylphosphine (134 mg, 0.449 mmol), palladium acetate (101 mg, 0.45 mml), and cesium carbonate (1.46 g, 4.49 mmol) in dioxane 25 ml (v/v 5/1) was kept at reflux temperature for 2 hours, then cooled to room 5 temperature, then filtered through celite, then concentrated and then purified by chromatography eluting with 12%MeOH/MeCI2/NH4OH to yield the product as a white solid (145 mg, 26%). 10 15 20 EXAMPLES 166 TO 179 25 Following procedures similar to those described herein, for example, Examples 85, 98, 137 and 136, the compounds in Table 14 were prepared. In Table 14 "Ex" represents "Example". Step 2 Preparation of 1 -[2-(2-methyl-4-thiazol-2-yl-piperazin-1 -yl)-2-oxo-ethyl]-pyrrolidine-3-carboxylic acid [3-(4-fluoro-phenyl)-1 H-indazol-6-yl]-amide Y-c,~y, o V-n A mixture of 3-methyl-1-thiazol-2-yl-piperazine (11 mg, 0.060 mmol), {3-[3-(4-fluorophenyl)-1 H-indazol-6-ylcarbamoyl]-pyrrolidin-1-yl}-acidic acid, trifluoroacetate (30mg, 0.06 mmol), EDCI.HCI (11 mg, 0.06 mmol), 1-hydroxybenzotriazole (9 mg, 0.066) mmol) and NMM (0.04 ml) was stirred in DMF (2ml) overnight at room temperature. The reaction was diluted with EtOAc (50 ml), washed with brine (20 ml), dried over MgS04, filtered and the solvent was evaporated. The resulting material was purified on reverse phase HPLC (C18 column), eluting with acetonitrile:water, yielding product which was dissolved in MeCI2 basified with saturated NaHC03, dried over MgS04, filtered and solvent evaporated yielding title product (10 mg). LCMS MH 548. Retention time: 2.36 minutes. RECIEVED IPONZ 22 AUGUST 2011 -284-TABLE 14 EX Structure MS (ESMS. MH) Retention time (min.) 166 ) )=o *L^f n \ ch3 (substitute Br—^ ^—F for ^ in Ex. 137, and see Ex. 85) 505 3.42 167 "/=o n \ ch3 (substitute Br—^ for in Ex. 137, and see Ex. 85) 487 3.34 168 tr\~j /=0 n \ ch3 (see Ex. 85 and Ex. 137) 494 2.43 RECIEVED IPONZ 22 AUGUST 2011 -285- 169 OJL ^ F ( F F\ 560 4.27 (substitute F—^ V-B(OH)2 for F—B(OH)2 in Ex. 98 and substitute s Br—(ft —f for in Ex- 137) 170 // \—N / 1 0 OMe (substitute H3CO—^^-B(OH)2 for 554 4.01 F—^~^—b(qh)2 in Ex. 98 and substitute gr——F f^'" in Ex. 137) 171 rQ-^ O^x F 542 4.11 (see Ex. 98 and substitute Br—\ y—F Br~-<rS>) for j5,_y in Ex. 137) RECIEVED IPONZ 22 AUGUST 2011 -286- 172 N=/ N-a (substitute (' y—B(OH)2 for F—B(OH)2 in Ex. 98 and substitute s Br—{3~F for ^ J in Ex" 137) 526 3.35 173 ry) o (substitute B(OH)2 for F—<Q>-B(OH)2 in Ex. 98) 526 1.51 174 />>OJVi (substitute B(OH)2 for F—<^^-B(OH)2 in Ex. 98) 542 1.59 175 ^■°anv o (substitute B(OH)2 for F—<^>-B(OH)2 in Ex. 98) 576 1.64 RECIEVED IPONZ 22 AUGUST 2011 -287- 176 yCt) /=o N \\ CH3 ^ (see Ex. 85 and Ex. 136) 567 3.16 177 rp~~> CUL -s N^/ o ■0 (substitute B(OH)2 for F—B(QH)2 in Ex. 98 and see Ex. 136) 586 3.85 178 0 OH S""^ (substitute B(OH)2 for F—B(OH)2 in Ex. 98 and see Ex. 132) 179 /k/ o \T T>A_ q b F (see Ex.98) EXAMPLES 181 and 183 to 259 Following procedures similar to those described herein, for example, Examples 5 1, 3 to 60, 85, 98, 128, 183, 184, the compounds in Table 15 were prepared. In Table 15 "Ex" represents "Example". RECIEVED IPONZ 22 AUGUST 2011 -288-TABLE 15 EX COMPOUND 181 p-/ 'CH3 183 n^/ 0 n N (substitute N^~^~B(OH)2 for F—^r~^—B(OH)2 in Ex. 98 and see Ex. 128) 184 \ c»> ryN <Y w f N~a (substitute CI—(' y for N C!—(' y~F in Ex. 128 and see Ex. 98) RECIEVED IPONZ 22 AUGUST 2011 -289- 185 fYY^A-Ti N J II I " V-x o U \=SN (see Ex. 183 and Ex. 184) 186 N 187 u/T ° • NY^1 n \j N—S\ / NH HO 188 °> \r N=/ \—N o vch3 N-a. (substitute Br—(' y for N=/ N-a. Ci—(' X)-F in Ex. 128 and N=/ see Ex. 85) recieved iponz 22 august 2011 -290 - 189 ■> n n\^^ch3 \ ch3 N^\ (substitute Br—(' y—ch3 for ci—(' Vf in Ex. 128 and see Ex. 85) 190 ,0-^0 ^ ^ N (substitute jf ^ for N ci N^N in Ex. 1 Step 6 and see Examples 3 to 60) 191 n-^C^r') ^ _y=\_yn=\ n* l_ 0 (see Examples 3 to 60 and Ex. 1) RECIEVED IPONZ 22 AUGUST 2011 -291 - 192 ox fl f* 7 /V o f 193 ° n S ^ /V V— n^^CH w f 194 rrv^o N ° ^NV^1 " v-\ vvs O TX V=n ^ ch3 195 rrY^^o N^t 0 N— r7 0 h3c-nn ch3 (see Ex. 1) RECIEVED IPONZ 22 AUGUST 2011 -292- 196 »-oa ^ v. /=o n ch3 197 iJ^'l ^ "^OvS a n*7 f 198 /rt-. 7 ^ _y=vv=\ l' vAHi o"q 199 'k>OJTBX>r 200 cjvojj; n-v 0 ^y*i vr> RECIEVED IPONZ 22 AUGUST 2011 -293- 201 fYY°^0 k-V ° "r"\ N^i xj N^ n"~\v r7 ° h2n 202 Vo N0 203 £<>><xVn o »o 204 vO' ~ 205 nQPi h3c RECIEVED IPONZ 22 AUGUST 2011 -294- 206 yYYcu<>0-0 n 0 n—' n=/ 0 207 \\ ^ n 208 ry) COrt, rv ^YV' f 209 rrNi ^n-V, or 0 Y> n=v-x n \ Q 0 210 /—\ 0 fl ^ N\ m n T \ H-~^y v^nh n--oh RECIEVED IPONZ 22 AUGUST 2011 -295- 211 ■or 0 n \ 1 0 F 212 H3C vU 213 j v 0 CH, <y ° w~i N f\ N Br 214 °> njT\-n k/^Y^i NC/ 215 yO^A^ iT^V"N t 7^ N=/ /CH3 V-o 0 RECIEVED IPONZ 22 AUGUST 2011 -296- 216 rvKKK _ .nv iAT ^ j) 0 n i f 217 £r XV f\ r° w ch3 f 218 & 1 ^ ' \ 0 219 & °-tx- C3 CHs 220 ° 0 o RECIEVED IPONZ 22 AUGUST 2011 -297- 221 A ocf3 222 »v ° " v» ^vs 223 ^ /t^v-n \ /-^ n f f 224 ° /—-i 0 /Vn "f U 225 rO- NY^ > O 0 \ o VNvJ( n n \ o<V* Oi. ch3 o RECIEVED IPONZ 22 AUGUST 2011 -298- 226 ~>cu.n . 227 ry> CUp, n JLH k^ywV O 228 ^yaa^ , 229 y Cxjc fv=/'* ii o 230 „^x RECIEVED IPONZ 22 AUGUST 2011 -299- 231 rryoJLo HO 232 ° / 1 0 ry}" "Y Tl N'A 233 / v 0 CH, <y ° N^F \r^N 234 ■if' A) F 235 'y xr RECIEVED IPONZ 22 AUGUST 2011 -300- 236 NV 0 N^J Q 237 D O $ o 238 d>-"°aO 6 239 £Y\ ^N'~X,;ON-_Yy N v / ^ \>ych- \— 0 v° 240 N=\ CH3 S -J/ F RECIEVED IPONZ 22 AUGUST 2011 -301 - 241 o H3C V 8 ^ N T ¥~\ F 242 ■'p-l-O , Ih, 0 Q O 243 . M l / 0 jTYY N J N=\^ HO 244 °yCS //~~N \ /==- jy • ^-~CH" \ / pu CH- N=( | 3 3 RECIEVED IPONZ 22 AUGUST 2011 -302- 245 fYYQJLp 0 v /n\ nx y ^ ^^ch2 \=^n 246 N^/ V^n w 247 /-v> Oio tyJ Vn-Y^i nA U ch3 i ci 248 rO-^ ^y° a ch3 249 % Oa _ XX ' ^ w ch' —ch3 RECIEVED IPONZ 22 AUGUST 2011 -303- 250 251 f 252 °H f 253 /^~~\^N-\ / \ /^\ /N=\ rv/ i VT^LHJ n^ 0 n °-ch3 254 rp~) cxv, >0 l^U'S n 11 xch, RECIEVED IPONZ 22 AUGUST 2011 -304- 255 0 ^ ^ n_/ \ °-ch3 256 // V\ I' y i y_Jy 0 f 257 ?-0"ni" nO"OaO 0 \__/ v_/ n_/ 258 ry-yCUQ^O-0 o \ ' > ' n—' n=/ VN 259 0 ry\ n=Y n-Y n \ ch3 RECIEVED IPONZ 22 AUGUST 2011 -305- EXAMPLES 260 TO 334 Using the intermediates made from Preparations 1 to 15 described below, and following the procedures described in the reaction Schemes described above, the compounds in Table 16 below were prepared. In Table 16 "Ex" represents "Example". Preparation 1 MeOoC Me°*C W 1D To a solution of LDA (33.5 mmol, 16.7 mL, 2 M in toluene) in 50 mL THF cooled at -78 deg C was added a solution of 1D (5.9 g, 25.7 mmol) in 50 mL THF dropwise. The crude was stirred at-78 deg C for 45 mins. To the crude was bubbled formaldehyde gas, freshly generated from cracking of para-formaldehde (12 g, 400 mmol). The crude was stirred at -78 deg C for an additional 30 mins. To the crude was added sat NH4CI (200 mL). The crude was warmed to rt. The crude was diluted in EtOAc. The organic layer was washed with brine and dried over MgS04, filtered, and conc. in vacuum. The crude was purified on Biotage using EtOAc/ hexane ( 3 : 7) -> EtOAc / hexane (1 : 1) to give 6.6 g (57%) of the product as a yellow oil. Preparation 2 o Me°2CV\/NB°C H0^OB0C OH 3D To a solution of ester 2D (2.5 g, 9.6 mmol) in MeOH (100 mL) was added 1 N NaOH (48 mL, 48.2 mmol) at rt. The crude was stirred at rt overnight. To the crude was added 1 N HCI (47.5 mL, 47.5 mmol). The crude was stirred at rt for 5 mins. PH of crude is made to 5 using PH paper. The crude was conc in vacuum and azeotropped 2X with toluene and dried under high vacuum for use in the HATU coupling with amine 4D in Preparation 3 below. RECIEVED IPONZ 22 AUGUST 2011 -306- Preparation 3 10 15 To a suspension of acid 3D and amine 4D (5.52 g, 12.5 mmol) in DMF (15 mL) and CH2CI2 (75 mL) was added DIPEA (5 mL, 28.8 mmol) and HATU (5.8 g, 12.5 mmol) at rt. The crude was stirred at rt overnight under a stream of nitrogen. To the crude was added brine and CH2CI2. The aq layer was extracted with EtOAc 2X. The combined organic layer was dried over MgS04, filtered, and conc in vacuum. To the crude was added MeOH (200 mL), THF (20 mL) and NaOH (1N, 25 mL, 25 mmol). The crude was stirred at rt for overnight. To the crude was added HCI (1N, 20 mL). The crude was stirred at rt for 5 mins. The crude was conc in vacuum and dissolved in H2O and CH2CI2. The aq layer was extracted with EtOAc 2 X. The combined organic layer was dried over MgS04, filtered, and conc in vacuum. The crude was purified on Biotage using EtOAc / hexane (2 : 5) -> EtOAc / hexane (3 : 2) to give 2.8 g (42%) of an off white solid 5D. MS (M+H+ = 697.25). Preparation 4 To a solution of alcohol 5D (3.9 g, 5.6 mmol) in CH2CI2 (65 mL) was added 20 solid NaHC03 (1.4 g, 16.8 mmol) and DMP (3.6 g, 8.4 mmol) at rt. The crude was stirred at rt for 1.5 hr. To the crude was added sat. sodium thiosulfate and sat. NaHC03 (150 mL : 150 mL) at rt. The crude was vigorously stirred at rt for 30 mins. The aq layer was extracted with CH2CI2 2X. The combined organic layer was washed with brine, dried over MgS04, filtered, and conc in vacuum to give 3.9 g of 6D 25 (quantitative). MS (M+H+, 695.24) RECIEVED IPONZ 22 AUGUST 2011 -307- Preparation 5 5 To a solution of crude aldehyde 6D (571 mg, 0.82 mmol) in MeOH (18 mL) was added K2CO3 (1.13 g, 8.2 mmol) and dimethyl-1-diazo-2-oxopropylphosphonate (prepared according to Miller, S.; Liepold, B.; Roth, G. J.; Bestmann, H. J. Synlett, 1996, 521-522) (474 mg, 2.5 mmol) at rt. The crude was stirred at rt for 1.5 hr. To the crude was added sat. NaHC03 and EtOAc. The aq layer was extracted with 10 EtOAc. The combined organic layer was washed with brine, dried over MgS04, filtered, and conc in vacuum. The crude was purified via prep plate using EtOAc / hexane (3 : 7) to give 408 mg of 7D (72%) as a white solid. LCMS (M+H+, 691.4, rt = 6.15) 15 Preparation 6 NBoc To a solution of crude aldehyde 6D (315 mg, 0.45 mmol) in THF (2 mL) was added 28% wt NH4OH (6 mL). The crude was stirred at rt for 2 mins before the addition of iodine (126 mg, 0.50 mmol). The crude was stirred at rt for 45 mins. The 20 crude was quenched with sat. Na2S03 and stirred vigorously for 15 mins. The crude was diluted in CH2CI2. The aq layer was extracted with CH2CI2. The combined organic layer was washed with aq NH4CI, brine, dried over MgS04, filtered, and conc in vacuum. The crude was purified via prep plate using EtOAc / hexane (2: 5) to give 139 mg of 8D (45%) as a yellow solid. MS (M+H+, 692.27). 25 RECIEVED IPONZ 22 AUGUST 2011 -308-Preparation 7 F F To a solution of crude aldehyde 6D (600 mg, 0.86 mmol) in THF (5 mL) cooled to -40 deg C was added a solution of Tebbe's reagent (0.5 mL, 0.25 mmol, 0.5 M 5 solution in toluene). The crude was warmed to 0 deg C in 1.5 hrs. The crude was diluted with ether and quenched with 1 N NaOH (1 mL, 1 mmol) at rt. The crude was stirred at rt for 10 mins. The crude was filtered through celite and concentrated in vacuum. The crude was purified via Biotage using EtOAc / hexane to give 165 mg of 9D (28%) as a yellow solid. MS (M+Na+, 715.24). 10 Preparation 8 F F To a solution of olefin 9D (60 mg, 0.086 mmol) in MeOH (10 mL) was added catalytic amount of 10 % wt palladium on carbon. The mixture was stirred under a 15 hydrogen atmosphere at room temperature overnight and filtered through celite. The filtrate was concentrated to provide 10D (47 mg). The material was used as such without further purification. MS (M+Na+, 717.28). Preparation 9 20 Preparation of 3-Prop-2-ynyl-pyrrolidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester y~i ^ y^\^NBoc O, o 1D 2E -NBoc RECIEVED IPONZ 22 AUGUST 2011 -309- Pyrrolidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester 1 (6 mmol) was dissolved in THF (20 mL) and cooled down to -78 °C in a dry ice-acetone bath. LDA (5 mL, 2.0 M, 10 mmol) was then added dropwise. The mixture was stirred at -78°C for 1 hr. Propargyl bromide (1.5 mL) was added in neat. The reaction was allowed to warm to rt naturally and stirred for 24 hrs. It was then quenched with sat. NH4CI solution, extracted with ethyl acetate 2 X 50 mL. The organic layer was washed with brine, dried (MgS04) and concentrated. The crude was purified on silica gel column using 4:1 hexanes/ethyl acetate to get the title compound (0.65 g) as an off-white gum. MS (267, M+H) Preparation 10 Preparation of 1 -{2-Oxo-2-[4-(4-pyrimidin-2-yl-phenyl)-piperazin-1 -yl]-ethyl}-3-(3H-[1,2,3]triazol-4-ylmethyl)-pyrrolidine-3-carboxylic acid [3-(4-fluoro-phenyl)-1 H-indazol-5-yl]-amide 1-{2-Oxo-2-[4-(4-pyrimidin-2-yl-phenyl)-piperazin-1-yl]-ethyl}-3-prop-2-ynyl-pyrrolidine -3-carboxylic acid [3-(4-fluoro-phenyl)-1H-indazol-5-yl]-amide 3E (0.085 g, RECIEVED IPONZ 22 AUGUST 2011 -310- 0.13 mmol) and Cul (1.3 mg) was suspended in 9:1 DMF/MeOH (1 mL) under Ar in a sealed vessel. TMSN3 (23 mg, 0.2 mmol) was then added. The mixture was heated at 100 oC overnight. After cooling to rt, the concentrated crude residue was purified by prep-TLC in 10% 2N-NH3/MeOH/CH2CI2 to yield 4E as a solid (36 mg). MS (686, M+H) Preparation 11 Preparation of 3-(3-Methoxy-propyl)-pyrrolidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester 3-Allyl-pyrrolidine-1,3-dicarboxylic acid 1 -tert-butyl ester 3-methyl ester 5E (538 mg, 2 mmol) was dissolved in THF (4 mL) and cooled to 0 oC. BH3 (3.8 mL, 1.0 M THF soln) was added in dropwise. After stirring at 0 oC for 15 mins, reaction was raised to rt for another 15 mins. 8 mL 1:1 EtOH/THF, 8 mL PH7 buffer and 8 mL 30 % H202 were then added sequentially. The mixture was stirred at rt overnight and then partitioned between ethyl acetate (50 mL) and brine (30 mL). The organic layer was dried and concentrated. The residue was purified on silica eluting with 2:1 to 1:1 hexanes/ethyl acetate to obtain 6E (326 mg) as a colorless oil. MS (310, M+Na). 3-(3-Hydroxy-propyl)-pyrrolidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester 6E (90 mg) was dissolved in a mixture of THF/DMF (1.5 mL/0.5 mL) at rt. Mel (0.1 mL) was added followed by NaH (40 mg, 40% suspension). After 90 mins, the reaction was quenched with sat. NH4CI soln and extracted with ethyl acetate. The organic layer was washed with brine, dried and conc. to yield 7E (96 mg) as a colorless oil. MS (324, M+Na). RECIEVED IPONZ 22 AUGUST 2011 -311 -Preparation 12 Preparation of 3-Fluoro-pyrrolidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester ,.n I \ LDA/PhS02NF _ /—\ "yp-r° O O q F o 5 n-Butyl lithium (2.5M/Hexanes, 3.83ml; 9.575 mmol) added dropwise to solution of diisopropylamine (1.36ml; 9.62mmol) at -78°C. Solution was allowed warm to room temperature and stirred for 30 minutes, then cooled to -78°C. A solution of Pyrrolidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester (2g, 8.72mmol) in THF (10ml) was added dropwise,warmed to -40°C for 1 hour,then cooled to -70°C.A 10 solution of N-fluorobenzene-sulfonimide (3.02g,9.57mmol) in THF (15ml) was added dropwise,stirred at -78°C for 1hour, then stirred at room temperature overnight. Precipitated solid was filtered,washed with EtOAc (2x150ml). Organic layer was washed with 1N HCI (30ml), brine (100ml), dried (MgS04), filtered and solvent evaporated. The residue was chromatographed on silica gel eluting with 10% v/v 15 EtOAc/hexanes yielding product as colorless oil (1.38g:64% yield). MS (ESMS.MH 249). Preparation 13 Preparation of 3-(1-Acetoxy-ethyl)-1-benzyl-pyrrolidine-3-carboxylic acid methyl 20 ester(3) TFA/MeCI2 /Sl N\ OMe 2F " YYCU3 Trifluoroacetic acid (0.5g, 4.38mmol) was added to a solution of methyl-3-acetoxy-2-methylenebutyrate (5g,29.03mmol) (1) and N-Methoxymethyl-N-25 trimethylsilylmethylbenzylamine (6.89g,29.03mmol) (2) in MeCI2 (100ml) at 0°C, then stirred overnight at room temperature.The solvent was evaporated,and residue extracted with EtOAc (200ml), NaHC03 (30ml and H20(100ml).The organic layer was separated,dried (MgS04),filtered and solvent evaporated yielding an oil which RECIEVED IPONZ 22 AUGUST 2011 -312- chromatographed on silica gel eluting with 30% v/v (EtOAc/hexanes) yielding product (3) as colorless oil (7.53g, 85% yield). ESMS MH, 306 (C17H23NO4) Preparation 14 Preparation of 1-Benzyl-3-(1-hydroxy-ethyl)-pyrrolidine-3-carboxylic acid (4) /° fl MeO-—A HO-—/' Lithium hydroxide (0.6g,14.29mmol) in H20 (5ml) was added to a solution of 3-(1-Acetoxy-ethyl)-1-benzyl-pyrrolidine-3-carboxylic acid methyl ester(3F) (2g, 6.55mmol) in THF:MeOH (5:1 v/v) (30ml) at room temperature, then refluxed for 1 hour. The solution was cooled and solvent evaporated yielding the product as the lithium salt of 4F. (2.0g, 100%) ESMS (MH, 250) Preparation 15 To a solution of 22G (1.54 g, 6.24 mmol) and TEA (1.16 mL, 8.11 mmol) in CH2CI2 (60 mL) cooled in an icebath was added chloroacetyl chloride (0.6 mL, 7.49 mmol) dropwise. The crude was stirred at 0 deg C for 10 mins. To the crude was added water. The layers were separated, and the aq layer was extracted with CH2CI2. The combined org. layer was washed with brine, dried over MgS04, filtered, and conc in vacuum to give 2.06 g of crude 23G. MS (M+H+, 317.4) 15 20 RECIEVED IPONZ 22 AUGUST 2011 -313 -TABLE 16 Ex Compound 260 261 Mass Spec (ESMS, MH): 628 Retention Time minutes: 2.27 262 Mass Spec (ESMS, MH): 645 Retention Time minutes: 2.96 RECIEVED IPONZ 22 AUGUST 2011 -314- 263 \ oh n f Mass Spec (ESMS, MH): 564 Retention Time minutes: 2.68 264 (\ /) \ L /Nv As V // OMe y y Mass Spec (ESMS, MH): 632 Retention Time minutes: 2.67 265 n-^4 OMe N-_y h3c7 0 Mass Spec (ESMS, MH): 612 Retention Time minutes: 3.01 266 /N~iDs ^ ° f^ll u N h v^n V O f Mass Spec (ESMS, MH): 572 Retention Time minutes: 2.5 RECIEVED IPONZ 22 AUGUST 2011 -315- 267 f ! y 0 ch, " V-\ Wx\ Q -J f Mass Spec (ESMS, MH): 638 Retention Time minutes: 2.68 268 Q -0 f Mass Spec (ESMS, MH): 624 Retention Time minutes: 2.61 269 /n i // 'n r^-\ y~N\ a /n—(\ ))—<\ /> r) > n Mass Spec (ESMS, MH): 632 Retention Time minutes: 2.51 RECIEVED IPONZ 22 AUGUST 2011 -316- 270 ■it' Ao f Mass Spec (ESMS, MH): 546 Retention Time minutes: 2.70 271 " A c( o O' Aa, Mass Spec (ESMS, MH): 658 Retention Time minutes: 2.88 272 xy n n=/ f Mass Spec (ESMS, MH): 566 Retention Time minutes: 2.66 273 RECIEVED IPONZ 22 AUGUST 2011 -317- ft ° Cu ^ "11 ^ f Mass Spec (ESMS, MH): 558 Retention Time minutes: 2.49 274 UyN Mass Spec (ESMS, MH): 660 Retention Time minutes: 2.54 275 /ss- o / \ n=\ V ° Q f Mass Spec (ESMS, MH): 704 Retention Time minutes: 3.72 RECIEVED IPONZ 22 AUGUST 2011 -318- 276 O ' n Mass Spec (ESMS, MH): 638 Retention Time minutes: 2.82 277 !P7p> O F n Mass Spec (ESMS, MH): 514 Retention Time minutes: 1.64 278 A h2c \ ' W ) N-V n Mass Spec (ESMS, MH): 620 Retention Time minutes: 3.25 RECIEVED IPONZ 22 AUGUST 2011 -319- 279 fl H,c ^ Y1 n Mass Spec (ESMS, MH): 622 Retention Time minutes: 3.27 280 O Mass Spec (ESMS, MH): 515 Retention Time minutes: 1.75 281 /=\ \_^0 Y o^P o n Mass Spec (ESMS, MH): 503 Retention Time minutes: 1.44 282 nc^./ \ [ n—' n ' n' X Xr O F n Mass Spec (ESMS, MH): 549 Retention Time minutes: 1.73 RECIEVED IPONZ 22 AUGUST 2011 -320 - 283 jf"J n-^A-ch3 n\ T f Mass Spec (ESMS, MH): 651 Retention Time minutes: 3.09 284 f / 1 0 ch, /kJ 0 \j Y ^ f Mass Spec (ESMS, MH): 561 Retention Time minutes: 2.62 285 n. 0 0 pA-V-JL-CV. 0 o ^—0 Mass Spec (ESMS, MH): 612 Retention Time minutes: 2.84 RECIEVED IPONZ 22 AUGUST 2011 -321 - 286 0 o ^—0 Mass Spec (ESMS, MH): 616 Retention Time minutes: 1.89 287 N\\ J ll 0 <y /y ^ YY x/ ^Y"S Mass Spec (ESMS, MH): 704 Retention Time minutes: 2.59 288 N\\ Jll 0 (jYv N—' N— I ]i O "N Mass Spec (ESMS, MH): 611 Retention Time minutes: 2.30 RECIEVED IPONZ 22 AUGUST 2011 -322- 289 ifYYp^O „Cf 0 H1 ^V*i vv-\ * o X^H Mass Spec (ESMS, MH): 628 Retention Time minutes: 2.25 290 h3c nAJ 0 o <0 X=^N Mass Spec (ESMS, MH): 630 Retention Time minutes: 2.54 291 X N't ° 'n v-x Q "A f Mass Spec (ESMS, MH): 663 Retention Time minutes: 3.22 RECIEVED IPONZ 22 AUGUST 2011 -323- 292 /V 0 XH o ^ \=^N Mass Spec (ESMS, MH): 626 Retention Time minutes: 2.31 293 <y ° XH " V-\ Q U f Mass Spec (ESMS, MH): 643 Retention Time minutes: 3.22 294 n2c. ,—v 0 0 W*i " v-s O \ssn f Mass Spec (ESMS, MH): 646 Retention Time minutes: 2.26 RECIEVED IPONZ 22 AUGUST 2011 -324- 295 h3c <T ° An n—\ vya/n. f Mass Spec (ESMS, MH): 665 Retention Time minutes: 3.24 296 h,c 0 ^NyON-Jtn-y hT ° " v-x Q U f Mass Spec (ESMS, MH): 649 Retention Time minutes: 3.15 297 h,c 3\ °~~~\ / \ ° fVNT^N~^NA <V 0 ^"Y^i N_\ Q X2 f Mass Spec (ESMS, MH): 649 Retention Time minutes: 3.16 RECIEVED IPONZ 22 AUGUST 2011 -325- 298 yGjy o O Aco Mass Spec (ESMS, MH): 513 Retention Time minutes: 2.66 299 1^0 v ■ 0 Mass Spec (ESMS, MH): 644 Retention Time minutes: 3.14 300 fvNYpN^N^i nV 0 K VV Q A f 301 ^YNYpNANy XJ 0 ?=\ n\ j n. n | ] Q U f Mass Spec (ESMS, MH): 686 Retention Time minutes: 2.79 RECIEVED IPONZ 22 AUGUST 2011 -326- 302 r\-y p nc-/ h3c || A \ ^YS n Mass Spec (ESMS, MH): 650 Retention Time minutes: 3.07 303 F Mass Spec (ESMS, MH): 662 Retention Time minutes: 3.05 304 0 /—-i 0 ch, NV H3C I 1 v3 n Mass Spec (ESMS, MH): 647 Retention Time minutes: 2.23 RECIEVED IPONZ 22 AUGUST 2011 -327- 305 ny h,c ^n Mass Spec (ESMS, MH): 561 Retention Time minutes: 1.86 306 n -\_j 0 H-c Xj ^n Mass Spec (ESMS, MH): 5.58 Retention Time minutes: 2.37 307 nc-/ h3c ^n Mass Spec (ESMS, MH): 525 Retention Time minutes: 2.68 RECIEVED IPONZ 22 AUGUST 2011 -328- 308 ch I 3 f 309 ch, I 3 0 r"° ^ \ JM-, o hs? I PX/ f 310 ch, I 3 0 r° N-J3^^ n// \ \\ V— \/N^y^N i 0 ^ f 311 ch, 0 NK>N>f ? /v 17 L Ij N f RECIEVED IPONZ 22 AUGUST 2011 -329- 312 ch, / 3 y^-J-OO f 313 ch / 3 f 314 NvCAir, o M „c'° ci || | UyS n^J Mass Spec (ESMS, MH): 666 Retention Time minutes: 3.70 315 "000 N-A „ C'° O ch3 3 T| ] Mass Spec (ESMS, MH): 646 Retention Time minutes: 2.70 RECIEVED IPONZ 22 AUGUST 2011 -330- 316 „ ".c rfv /^Y N-Y^CH3 N\ I Mass Spec (ESMS, MH): 660 Retention Time minutes: 2.48 317 HC\ <V 0 Q Vx f Mass Spec (ESMS, MH): 647 Retention Time minutes: 2.98 318 ch, Q ^ f Mass Spec (ESMS, MH): 663 Retention Time minutes: 2.79 RECIEVED IPONZ 22 AUGUST 2011 -331 - 319 J o ^ V 0 c> 320 ,NV1 NV^/^N Q >70UU H/ ° Y % Mass Spec (ESMS, MH): 662 Retention Time minutes: 2.73 321 jfyvQ'^pi N\ / i II i N=\ CH3 o \s^N Mass Spec (ESMS, MH): 660 Retention Time minutes: 1.93 RECIEVED IPONZ 22 AUGUST 2011 -332- 322 A^ 0 X n T ^0 ji ^ N:A^ ^3 AA^n^ Q A f Mass Spec (ESMS, MH): 677 Retention Time minutes: 2.70 323 -O^L y v h3c oh A ^ U/ 0 v3 f n^l Mass Spec (ESMS, MH): 649 Retention Time minutes: 2.72 324 rr f Mass Spec (ESMS, MH): 619 Retention Time minutes: 3.61 RECIEVED IPONZ 22 AUGUST 2011 -333- 325 rr ^5 n J f Mass Spec (ESMS, MH): 621 Retention Time minutes: 3.69 326 f \ /—\ 0 w f Mass Spec (ESMS, MH): 568 Retention Time minutes: 3.52 327 HCy vCLi* XX Q. n Jj % Q O f Mass Spec (ESMS, MH): 658 Retention Time minutes: 2.68 RECIEVED IPONZ 22 AUGUST 2011 -334- 328 /v n n \ rvN t i <V v% \ / n j n— f Mass Spec (ESMS, MH): 581 Retention Time minutes: 2.95 329 ^y^OJU <V ° 'N V--\ Ct J-X f Mass Spec (ESMS, MH): 648 Retention Time minutes: 3.18 330 ch3 q rf ^V) N\ J f Mass Spec (ESMS, MH): 635 Retention Time minutes: 3.82 RECIEVED IPONZ 22 AUGUST 2011 -335- 331 9 p 332 N^l^l >\,0 U jyv oo Mass Spec (ESMS, MH): 481 Retention Time minutes: 2.55 333 0>"O u O " ^ 334 °>nO U Q " F F RECIEVED IPONZ 22 AUGUST 2011 -336- EXAMPLE 335 Tr F F To a solution of 7D (Preparation 5 in Examples 260-334) (206 mg, 0.30 mmol) in CH2CI2 (3 mL) was added TFA (3 mL). The crude was stirred at rt for 2 hrs. The 5 crude was partially conc in vaccum. The crude was quenched with MeOH (5 mL). The crude was conc in vaccum and azeotroped with toluene 2X and dried under high vac prior to further use. To this crude amine and TEA (0.3 mL, excess) in dioxane (2 mL) was added crude 23G (Preparation 15 in Examples 260-334) (132 mgs, 0.42 mmol) at rt. The crude was stirred at 80 deg C under nitrogen overnight. The crude 10 was quenched with water and diluted in EtOAc. The layers were separated, and the aq layer was extracted with CH2CI2 2X. The combined org. layer was washed with brine, dried over Na2S04, filtered, and conc in vaccum. The crude was purified via prep plate using 2M NH3 in MeOH / CH2CI2 (5 / 95) to give 116 mgs (62%) of an off white solid. LCMS (M+H+, 647.4, retention time = 2.98 min) Preparation of 3-Methoxymethyl-1 -{2-[4-(4-pyrimidin-2-yl-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-acetyl}-pyrrolidine-3-carboxylic acid [3-(2-cyclopropyl-pyridin-4-yl)- 15 EXAMPLE 336 O ' \\ 0 I ' HN 1 H-indazol-5-yl]-amide 20 RECIEVED IPONZ 22 AUGUST 2011 -337- 1. TFA, 90°C 2. (Boc)20, Et3N, CH2CI2, r.t. * (quant.) Br 3. PdCI2dppf, Bis(pinacolate)diboron DMSO, KOAc, 100°C || then add Pd(Ph3P)4, K2C03, H20, 100 °C 4. TFA-CH2CI2, r.t. » (71%) N H TFA salt RECIEVED IPONZ 22 AUGUST 2011 Procedure for the Preparation of 2-r4-(1.2,3,6-Tetrahvdro-pyridin-4-vl)-phenvll-pyrimidine trifluoroacetic acid salt Step 1: 4-(4-Bromophenyl)-4-piperidinol (68g, 0.27 mol) was added in small portions to a solution of trifluoroacetic acid (205 ml) at r.t. and the mixture was heated at 90 °C for 2 hr. Solvents were then removed in vacuum to give 4-(4-bromophenyl)-1,2,3,6- RECIEVED IPONZ 22 AUGUST 2011 -339 - tetrahydropyridirie as pale yellow oil. The yellow oil was used in the next step without further purification. Step 2: 4-(4-Bromophenyl)-1,2,3,6-tetrahydropyridine (crude from step 1) was stirred 5 in dichloromethane (500 ml) at r.t. Triethylamine (148ml, 1.06 mol) followed by (Boc)20 (87g, 0.40 mol) were added. The suspension slowly dissolved and the yellow solution was stirred at r.t. for 2 hr. The mixture was washed with water (X2), dried (MgS04) and chromatograph through a short pad of silica. The fractions with the product 4-(4-Bromophenyl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester 10 were combined and solvents were removed in vacuum to give pale yellow oil which solidified on standing at r.t. to become white solid (91 g, quant.) 3. PdCI2dppf, Bis(pinacolate)diboron DMSO, KOAc, 100°C then add Pd(Ph3P)4, K2C03, HzO, 100 °C 4. TFA-CH2CI2, r.t. • N^N (71%) H TFA salt 15 Step 3: 4-(4-Bromophenyl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (19.5g, 0.058mol), bis(pinacolate)diboron (22.Og, 0.086 mol), PdCI2(dppf).CH2Cl2 (4.74g, 0.0058mol), potassium acetate (17.0g, 0.17mol) were weighted into a 1L 2-necked round bottomed flask equipped with a reflux condenser. Methyl sulfoxide (400ml) was added and the mixture was purged with nitrogen for 20 min before it was 20 heated at 100 °C for 2 hr under nitrogen. The mixture was cooled to r.t. Potassium carbonate (40g, 0.29mol), 2-bromopyrimidine (11.0g, 0.070mol) and water (200ml) were added. The mixture was again purged with nitrogen for 20 min. Palladium tetrakistriphenylphosphine (2.4g, 0.0029mol) was added and the final mixture was stirred at 100 °C for a further 2 hr. After being cooled to r.t., ethyl acetate and water 25 were added. The mixture was filtered through a pad of Celite. Layers were separated and the organic layer was washed with water (X2). The combined aqueous layers were extracted with ethyl acetate (X1). The combined organic layers were stirred with enough charcoal to give a yellow solution. The mixture was filtered through a pad of RECIEVED IPONZ 22 AUGUST 2011 -340- Celite and the solvents in the filtrate were removed in vacuum to give 4-(4-pyrimidin-2-yl-phenyl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester as dark brown oil. Step 4: 4-(4-pyrimidin-2-yl-phenyl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl 5 ester (crude from step 3) was dissolved in dichloromethane (200ml) and trifluoroacetic acid (22ml, 0.29mol) was added at r.t. The mixture was stirred at r.t. for 5 hr and solvents were removed in vacuum. Diethyl ether was added and off-white solid was formed. The solid was filtered and washed with diethyl ether to give a salt (14.4g, 71%). 0 Preparation of 2-Chloro-1 -[4-(4-pyrimidin-2-y!-phenyl)-3,6-dihydro-2H-pyridin-1 -yl]-ethanone 15 2-[4-(1,2,3,6-Tetrahydro-pyridin-4-yl)-phenyl]-pyrimidine trifluoroacetate ( 2.3 g, 9.7 mmol) was dissolved in 75 ml of dichloromethane and 4.1 ml of triethylamine added at 0 C. Chloroacetylchloride (0.92 ml, 11.7 mmol) was added and the reaction mixture stirred for 30 min. The reaction mixture was washed with a solution of saturated sodium bicarbonate (80 ml), the organic layer separated, dried over 20 magnesium sulfate and evaporated to obtain 2.41 g of crystalline product. RECIEVED IPONZ 22 AUGUST 2011 -341 - Chiral salt resolution of 3-methoxy-pyrrolidine-3-carboxylic acid methyl ester ft , ho2c oh ( ^ ho c02h Methanol / O O' o A / .0 "02C OH n+h2 )—( HO C02H Crystal 10 To a solution of 3-Methoxymethyl-pyrrolidine-3-carboxylic acid methyl ester (6.1 g, 35.8 mmol) in methanol (50 mL) was added L-tartaric acid (5.11 g, 34 mmol) and the formed mixture was sonicated to ensure the dissolve of tartaric acid. The solution was left standing at room temperature and crystals started forming after less than 10 minutes. After standing at RT for over night, the formed crystal was filtered, washed with cold methanol and was re-crystallized using 25 mL of methanol to give 2.2 gram material. Preparation of 3-Methoxymethyl-1 -{2-[4-(4-pyrimidin-2-yl-phenyl)-3,6-dihydro-2H-15 pyridin-1 -yl]-acetyl}-pyrrolidine-3-carboxylic acid methyl ester o V- NH.tartrate O TEA/CH3CN 3-Methoxymethyl-pyrrolidine-3-carboxylic acid methyl ester tartaric acid salt ( 1.54 gm, 4.85 mmol) in 25 ml of acetonitrile was added 2-Chloro-1-[4-(4-pyrimidin-2-20 yl-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-ethanone (2.2 gm, 5.82 mmol), triethylamine (3.4 ml, 24.3 mmol) and the reaction mixture stirred at 80 C for 18 hrs. The reaction mixture was evaporated, and extracted into dichloromethane from water. The dichloromethane extracts were dried over Na2S04, filtered and evaporated. The mixture was chromatographed on silica gel using 2-3 % MeOH/dichlormethane to 25 obtain 1.5 gm of title compound. RECIEVED IPONZ 22 AUGUST 2011 -342- Preparation of 3-(2-Chloro-pyridin-4-yl)-5-nitro-1-trityl-1 H-indazole ci 10 15 3-Bromo-5-nitro-1-trityl-1 H-indazole (24.3 gm, 50 mmol) was stirred and degassed under nitrogen in dioxane/water (150/ 60 ml). Pyridine-2-chloro-4-boronic acid (8.7 gm, 55 mmol), Pd(dppf)CI2 ( 4.1 gm, 5 mmol) and K3P04 (26.5 g, 125 mmol) added. The reaction mixture was stirred at 80 C for 18 hrs. The reaction mixture was evaporated to dryness,, dissolved in dichloromethane, filtered through a silica gel plug and washed with 20% ethylacetate/hexanes to obtain 22 gm of title product. Preparation of 3-(2-Cyclopropyl-pyridin-4-yl)-5-nitro-1-trityl-1 H-indazole To a tube under nitrogen was added 36.2 ml ZnCI2 (0.5 M in THF,18.02 mmol) followed by cyclopropylmagnesium bromide ( 34 ml of 0.5 M in THF soln., 16 mmol). The resultant mixture was stirred for 20 min at r.t. NMP ( 23 ml) was added, stirred for 5 min followed by 3-(2-Chloro-pyridin-4-yl)-5-nitro-1 -trityl-1 H-indazole (5.5 gm, 10.6 mmol) and Pd[P(tBu)3]2 ( 0.108 gm, 0.22 mmol). The tube was sealed under nitrogen and stirred at 100 C for 18 hrs. The reaction mixture was then cooled and evaporated to dryness. Silica gel chromatography using 5-20% ethylacetate/hexanes gave 2.1 g of title product. RECIEVED IPONZ 22 AUGUST 2011 -343- Preparation of 3-(2-Cyclopropyl-pyridin-4-yl)-1 -trityl-1 H-indazol-5-ylamine 5 3-(2-Cyclopropyl-pyridin-4-yl)-5-nitro-1 -trityl-1 H-indazole (2 gm) was dissolved in 20 mol of 50% methanol/toluene and balloon hydrogenated for 18 hrs in the presence of 0.4 gm of 50% by weight 10% Pd/C. The reaction mixture was filtered and evaporated to give the title product. 10 Preparation of 3-Methoxymethyl-1-{2-[4-(4-pyrimidin-2-yl-phenyl)-3,6-dihydro-2H-pyridin-1 -yl]-acetyl}-pyrrolidine-3-carboxylic acid [3-(2-cyclopropyl-pyridin-4-yl)-1 -trityl-1 H-indazol-5-yl]-amide 15 acetyl}-pyrrolidine-3-carboxylic acid methyl ester (500 mg, 1.11 mmol) was added to a solution of 10 ml of 50% methanol/dichloromethane. 5 mL of 1N NaOH was added 20 and the reaction mixture stirred for 18 hrs. 5.5 ml of 1N HCI was added and the RECIEVED IPONZ 22 AUGUST 2011 -344- reaction mixture evaporated to dryness. To the crude reaction mixture was added 3-(2-Cyclopropyl-pyridin-4-yl)-1-trityl-1 H-indazol-5-ylamine (601 mg, 1.22 mmol), HATU (464 mg, 6.66 mmol), triethylamine (0.93 ml, 6.66 mmol) and 10 ml of 50% N,N-dimethylformamide/dichloromethane. The reaction mixture was stirred for 18 hrs. 5 followed by washing with brine and extracted with ethylacetate 3X. After evaporation of the organic layers, the crude reaction mixture was chromatographed on silica gel using 1-3% 2N NH3/methanol/dichlormethane as the eluent to obtain 570 mg of title product. 10 Preparation of 3-Methoxymethyl-1 -{2-[4-(4-pyrimidin-2-yl-phenyl)-3,6-dihydro-2H-pyridin-1 -yl]-acetyl}-pyrrolidine-3-carboxylic acid [3-(2-cyclopropyl-pyridin-4-y!)-1 H-indazol-5-yl]-amide 3-Methoxymethyl-1-{2-[4-(4-pyrimidin-2-yl-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-acetyl}-pyrrolidine-3-carboxylic acid [3-(2-cyclopropyl-pyridin-4-yl)-1 -trityl-1 H-indazol-5-20 yl]-amide ( 570 mg, 0.63 mmol) was dissolved in 4 ml of trifluoroacetic acid (TFA), 10 ml dichloromethane and 2 ml of water and the reaction mixture was stirred for 18 hrs. The reaction mixture was evaporated and chromatographed on silica gel using 3-5% RECIEVED IPONZ 22 AUGUST 2011 -345- 2N NH3/methanol/dichlormethane to obtain 444 mg of title product. MS (M+1)= 669. Retention time (minutes) 2.67. Scheme 13 Preparation of 3-(3.6-Dihvdro-2H-pyran-4-vO-1 -trityl-1 H-indazol-5-vlamine and 3-(Tetrahvdro-pyran-4-vl)-1 -tritvl-1 H-indazol-5-vlamine Step 1: Preparation of Trifluoro-methanesulfonic acid 3,6-dihydro-2H-pyran-4-yl ester To a solution of 4-tetrahydropyranone (2g, 0.02 mol) in THF (10 mL) at -78 "C, LiHMDS (1 M, 11 ml) was added dropwise through a syringe. The formed solution was then stirred at -78 "C for about 1 hour. The re action was warmed up to room temperature briefly and was cooled back to -78 "C. Then 2-[N, N-bis(trifluoromethylsulfonyl)amino]-5-chloropyrine (7.85 g, 0.02 mol) was added in four portions. The resulted reaction mixture was gradually warmed up to room temperature and was stirred for overnight. After removal of solvent, the residue was purified using chromatography (eluted with DCM/Hexane = 80/20) to give product as a colorless oil Step 2: Preparation of 4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyran A 250 mL round bottom flask containing trifluoro-methanesulfonic acid 3, 6-dihydro-2H-pyran-4-yl ester (2.7 g, 11.6 mmol), PdCl2(dppf) (440 mg, 0.6 mmol) and potassium acetate (3g, 36 mmol) in dioxane (20 mL) was flushed with Ar three times. Tr (3g). RECIEVED IPONZ 22 AUGUST 2011 -346- The reaction mixture was heated at 80 'C for overni ght. After the reaction was cooled to room temperature, the reaction mixture was filter through a column packed with celite and the filtrate was concentrated. The residue was purified using column chromatography (10 % hexane in dichloromethane) and product was obtained as 5 white solid (2g, 81% yield). Step 3: Preparation of 3-(3,6-Dihydro-2H-pyran-4-yl)-5-nitro-1 -trityl-1 H-indazole A mixture containing 4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyran (0.8 g, 3.8 mmol), 3-Bromo-5-nitro-1 -trityl-1 H-indazole (2g, 4.0 10 mmol), PdCI2(dppf) (150 mg, 0.2 mmol) and potassium phosphate (2.6 g, 12 mmol) in dioxane (10 mL) was flushed with Ar and was heated at 80 'C for overnight under Ar. LC-MS indicated the completion of reaction and the mixture was filter through celite. The filtrate was concentrated and was purified on a column (10 hexane in dichloromethane) to give 1.2 g of product (64 % yield). 15 Step 4: Preparation of 3-(3,6-Dihydro-2H-pyran-4-yl)-1-trityl-1 H-indazol-5-ylamine and 3-(Tetrahydro-pyran-4-yl)-1 -trityl-1 H-indazol-5-ylamine To a solution of 3-(3,6-Dihydro-2H-pyran-4-yl)-5-nitro-1-trityl-1 H-indazole (100 mg, 0.2 mmol) in methanol was added and Pd/C (10%, 20 mg). The reaction mixture 20 was evacuated under vacuum and hydrogen gas was filled. After repeated three times the reaction was kept under hydrogen atmosphere overnight at room temperature. LCMS showed the starting material was consumed completely and both 3-(3,6-dihydro-2H-pyran-4-yl)-1-trityl-1 H-indazol-5-ylamine and 3-(tetrahydro-pyran-4-yl)-1-trityl-1H-indazol-5-ylamine were obtained. The two products were separated using 25 prep-HPLC to give both product in 60 % and 40 % yield respectively. Preparation 16 Stepl: Preparation of (2-Nitrophenyl)-(2-trimethylsilanylthiazol-5-yl)methanone O NO? 30 To a solution of 2-trimethylsilylthiazole (2.0 g, 12.7 mmol) in THF at -78 C was added BuLi (5.08 mL, 2.5 M, 12.7 mmol). The reaction was stirred at -78 C for 0.5 hr recieved iponz 22 august 2011 -347- and methyl 2-nitrobenzoate (2.69 mL, 19.1 mmol) was added. The suspension was stirred at room temperature for 2 hr and quenched with ammonium chloride solution. The mixture was extracted with ethyl acetate and the combined organic layer was dried over sodium sulfate, concentrated and purified by column chromatography to 5 give 2H (680 mg) 10 15 20 Step2: Preparation of (2-Aminophenyl)-thiazol-5-yl-methanone o no? o nh? nil OH / To a solution of 2H (631 mg, 2.72 mmol) in ethanol/H20 (12 mL/0.5 mL) was added iron (1.5 g, 27.2 mmol), then concentrated HCI (0.5 mL). The reaction was heated to reflux for 2.5 hr and filtered. The filtrated was neutralized with 1.0 N NaOH (5 mL) and extracted with ethyl acetate. The combined organic layer was dried over sodium sulfate, concentrated and purified by column chromatography to give 3H (280 mg) Step 3: Preparation of 3-Thiazol-5-yl-1 H-indazole o nh2 NaN02, 50% H2S04 then SnCI2 3H N^/ 4H To a solution of 3H (241 mg, 0.103 mmol) in 3 mL of 50% sulfuric acid at 0 C was added sodium nitrite (97.4 mg, 0.125 mmol). The reaction was stirred at 0 C for 1 hr and room temperature for 5 minutes and chilled to 0 C. To this was added SnCI2 (673 mg, 0.310 mmol) and stirred at 0 C for 1 hr. The suspension was diluted with water and extracted with ethyl acetate. The combined organic layer was washed with 1 N NaOH solution, dried over sodium sulfate, concentrated and purified by column chromatography to give 4H (149 mg) 25 RECIEVED IPONZ 22 AUGUST 2011 -348- Step 4: Preparation of 5-Nitro-3-thiazol-5-yl-1 H-indazole h2so4 knoq N^/ 4H 5H To a solution of 4H (149 mg, 0.74 mmol) in 2 mL of concentrated sulfuric acid at 0 C was added potassium nitrate (82.3 mg, 0.81 mmol). The reaction was stirred at room temperature for 2.5 hr and poured into ice water. The yellow solid was collected through filtration and dried under vacuum to afford 5H (98 mg) Step 5: Preparation of 3-Thiazol-5-yl-1H-indazol-5-ylamine no, H2, Pd/C, MeOH Nci/ --- Ncs/~ A suspension of 5H (98 mg, 0.39 mmol) and catalytic amount of Pd on carbon (5%) in methanol was stirred under a hydrogen atmosphere overnight and filtered through celite. The filtrate was concentrated to provide 6H (62 mg) Preparation 17 Step 1: Preparation of 3-(3-Trifluoromethylphenyl)-5-nitro-1-trityl-1 H-indazole Pd(PPh3)4, Na2C03 ► cf3 no2 (ho)2b A suspension of 7H (200 mg, 0.413 mmol), 3-trifluoromethylphenylboronic acid (94 mg, 0.498 mmol), Pd(PPh3)4 (48 mg, 0.041 mmol) and 2 M sodium carbonate (0.45 mL) in 3 mL of dioxane/EtOH/H20 (7/3/2) was heated to 150 C for 10 minutes using microwave. The reaction was partition between ethyl acetate and water. The RECIEVED IPONZ 22 AUGUST 2011 -349- organic layer was dried over sodium sulfate, concentrated and purified by column chromatography to afford 8H (189 mg) Step 2: Preparation of 3-(3-Trifluoromethyl-phenyl)-1 -trityl-1 H-indazol-5-ylamine H2 Pd/C MeOH A suspension of 8H (189 mg, 0.350 mmol) and catalytic amount of Pd on carbon (5%) in methanol was stirred under a hydrogen atmosphere overnight and filtered through celite. The filtrate was concentrated to provide 9H (139 mg) 10 Step 3: Preparation of 3-(3-Trifluoromethyl-phenyl)-1H-indazol-5-ylamine 15 20 TFA/DCM A solution of 9H (139 mg, 0.268 mmol) in 2 mL of TFA/DCM (1/1) was stirred at room temperature for 1 hr and concentrated. The residue was purified by column chromatography to afford 10H (61.7 mg) Preparation 18 Preparation of 3-(4-Methoxv-3-trifluoromethvl-phenvn-1 H-indazol-5-vlamine 3-(4-Methoxy-3-trifluoromethyl-phenyl)-1 H-indazol-5-ylamine was prepared using essentially the same scheme for preparing 10H. The boronic acid for the first step was 4-methoxy-3-trifluoromethylphenylboronic acid. RECIEVED IPONZ 22 AUGUST 2011 -350- Preparation 19 Preparation of 3-Cvclohexvl-1H-indazol-5-vlamine H Nx 3-Cyclohexyl-1H-indazol-5-ylamine was prepared using essentially the same scheme for preparing 10H. The boronic acid for the first step was 1-cyclohexene-boronic acid. 3-(2-Fluoro-pyridin-4-yl)-1H-indazol-5-ylamine was prepared using essentially the same scheme for preparing 10H. The boronic acid for the first step was 3-fluoro-4-pyridineboronic acid pinacol ester. Preparation 21 Preparation of 4-fluoro-4-thiazol-2-vl-piperidine-1 -carboxylic acid tert-butyl ester 71 4-Hydroxy-4-thiazol-2-yl-piperidine-1-carboxylic acid tert-butyl ester 61 (500 mg, 1.76 mmol) was dissolved in CH2CI2 (20 mL) and cooled to 0 °C. DAST (0.46 mL, 3.52 mmol) was then added. The mixture was stirred at 0 °C for 1 hr and then Preparation 20 Preparation of 3-(2-Fluoro-pvridin-4-vl)-1H-indazol-5-vlamine H F Boc 71 Boc 61 RECIEVED IPONZ 22 AUGUST 2011 -351 - quenched with sat. NaHC03. The separated organic layer was dried and concentrated in vacuo. The crude was purified with silica gel column (eluting with 12.5% ethyl acetate in hexanes) to yield an off-white solid (443 mg) as the title compound. Preparation 21A Step 1: n-BuLi THF, -78 °C then add 9 Cj Br f|^j Boc (80%) Br Boc To a solution of 1,4-dibromobenzene (1.0g, 4.24 mmol) in tetrahydrofuran (10ml) at -78 °C under nitrogen, a solution of n-butyl lithium (1.7 ml, 4.24 mmol, 1,6M in hexane) was added slowly. The mixture was allowed to warm from -78 °C to -20 °C in 1 hr. A solution of piperidone (703mg, 3.53 mmol) in tetrahydrofuran (5 ml) was dded at -78 °C and the mixture was stirred at the same temperature for 1 hr. Saturated ammonium chloride solution was added and the mixture was allowed to warm to r.t. Water and ethyl acetate were added and layers were separated. The aqueous layer was extracted with ethyl acetate (X2), The combined organic layers were dried (MgS04) and filtered. Solvents were removed in vacuum and column chromatography [ethyl acetate - hexane, 5:1 (v/v)] gave 4-(4-bromophenyl)-4-hydroxypiperidine-1-carboxylic acid tert-butyl ester (1.0g, 80%) as colorless oil. Step 2: 1. PdCI2dppf, Bis(pinacolate)diboron DMSO, KOAc, 100°C then add Pd(Ph3P)4, K2C03, H20, 100 °C 2. TFA-CH2CI2, r.t. (80%) 4-(4-bromophenyl)-4-hydroxypiperidine-1-carboxylic acid tert-butyl ester (800mg, 2.25mmol), bis(pinacolate)diboron (856mg, 3.37 mmol), PdCI2(dppf).CH2CI2 RECIEVED IPONZ 22 AUGUST 2011 -352- (184mg, 0.23mmol), potassium acetate (660mg, 6.74mmol) were weighted into a sealed-tube. Methyl sulfoxide (20ml) was added and the mixture was purged with nitrogen for 20 min before it was heated at 100 °C for 2 hr under nitrogen. The mixture was cooled to r.t. Potassium carbonate (1.55, 11.2mmol), 2-bromopyrimidine 5 (429mg, 2.70mmol) and water (10ml) were added. The mixture was again purged with nitrogen for 20 min. Palladium tetrakistriphenylphosphine (260mg, 0.23mmol) was added and the final mixture was stirred at 100 °C for a further 2 hr. After being cooled to r.t., ethyl acetate and water were added. The mixture was filtered through a pad of Celite. Layers were separated and the organic layer was washed with water 10 (X2). The combined aqueous layers were extracted with ethyl acetate (X1). The combined organic layers were dried (MgSC>4) and filtered. Solvents were removed in vacuum and column chromatography [ethyl acetate - hexane, 1:1 (v/v)] gave 4-hydroxy-4-(4-pyrimidin-2-ylphenyl)-piperidine-1-carboxylic acid tert-butyl ester (639mg, 80%) as colorless oil. 15 Preparation 22 Preparation of 4-methoxv-4-(4-pvrimidin-2-vl-phenyl)-piperidine-1 -carboxylic acid tert-butyl ester 91 20 4-Hydroxy-4-(4-pyrimidin-2-yl-phenyl)-piperidine-1 -carboxylic acid tert-butyl ester 81 (138 mg, 0.39 mmol) was dissolved in DMF (2 mL) and cooled to 0 °C. Mel (0.1 mL) was added followed by the addition of NaH (26 mg, 60% suspension in mineral oil). After 30 min at 0 °C, the reaction was quenched with sat. NH4CI and extracted with ethyl acetate. The combined organic layers was washed with brine, 25 dried and concentrated in vacuo. The residue was purified with prep TLC plates (developing with 50% ethyl acetate/hexanes) to yield a colorless film (80 mg) as the title compound. RECIEVED IPONZ 22 AUGUST 2011 -353- Preparation 23 Preparation of 4-bromo-2.6-dimethvl-pvridine 11 OH Br 5 2,6-Dimethyl-pyridin-4-ol 101 (6.16 g, 50 mmol), PBr5 (11.9 g, 27.65 mmol) and POBr3 (2.5 mL, 24.6 mmol) was combined and CHCI3 (2.5 mL) was added. The reaction was heated at 100 °C for 5 hrs and then cooled in an ice bath. Solid KOH was added till PH reached 7-8 followed by extraction with Et20 (3x75 mL). The combined ether layer was dried and evaporated in vacuo to give a thick clear crude oil 10 (10.1 g) as the title compound. Preparation 24 Preparation of 2.6-dimethvl-4-pyridine boronic acid 12 15 4-Bromo-2,6-dimethyl-pyridine (910 mg, 4.9 mmol) and triisopropyl borate (2.3 mL, 10 mmol) in THF (10 mL) were cooled in a -78 °C bath. BuLi (2.7 M, 7 mL) was added in drop wise. After 3 hrs, the bath was removed. The reaction was acidified with 1N HCI till pH =1. The separated aqueous layer was neutralized with NaOH and subsequently extracted with ethyl acetate. A crude white solid was obtained (800mg) 20 as the title compound. RECIEVED IPONZ 22 AUGUST 2011 -354 Preparation 25 Preparation of 2-trifluoromethvl-4-pvridine boronic acid 14 HOv. ^OH B •CF3 141 The title compound was prepared from 2-trifluoromethyl-pyridin-4-ol (131) by a procedure essentially similar to that described in Chem. Het. Cpds, 1997, p. 995, the disclosure of which is incorporated herein by reference thereto. EXAMPLE 337 Step 1: Synthesis of 2-allyloxy-acrylic acid ethyl ester COOEt ^A-COOEt NaOH - k + ,Me THF/H20 Me7 Me The (2-allyloxy-2,2-bis-ethoxycarbonyl-ethyl)-trimethyl-ammonium iodide was prepared according to a procedure essentially similar to that described in J. Am. Chem. Soc. 1987, 109, 1170-1186, the disclosure of which is incorporated herein by reference thereto. At 0 C, a solution of NaOH (1N, 6 ml) was added into a stirred solution of (2-allyloxy-2,2-bis-ethoxycarbonyl-ethyl)-trimethyl-ammonium iodide (2.1 g) in DMSO and water (9:1, 35 ml) and resulting solution was allowed to stir at room temperature overnight. The reaction mixture was diluted with ether, washed with RECIEVED IPONZ 22 AUGUST 2011 -355- water three times, brine and dried (MgS04). After evaporation of solvent, the title compound (431 mg) was obtained. Step 2: Synthesis of 3-allyloxy-1-benzyl-pyrrolidine-3-carboxylic acid ethyl ester COOEt EtOOCN/ | + MeO^N^SiMe3 ^ 0/\^NBn ° /> 5 \ To a stirred solution of the 2-allyloxy-acrylic acid ethyl ester (431 mg) and N- (methoxymethyl)-A/-(trimethylsilylmethyl)benzylamine (847 j_lI) in dichloromethane (10 ml) was added at 0 °C trifluoroacetic acid (21 j_lI). The resulting solution was warmed to room temperature and stirred overnight. The crude product was purified by column 10 chromatography on silica gel, eluted with a solution of ethyl acetate in hexanes (25-100%) to give the title compound (341 mg). Step 3: Synthesis of 3-propoxy-pyrrolidine-3-carboxylic acid ethyl ester EtOOCN/~~~~| EtOOCN/~~~~| QV-NBn Q/V-NH i 15 A mixture of 3-allyloxy-1-benzyl-pyrrolidine-3-carboxylic acid ethyl ester (145 mg), ammonium formate (126 mg), 10% Pd/C (20 mg) and methanol (4 ml) was refluxed for 40 minutes. The mixture was filtered through Celite, washed with ethyl acetate. The combined filtrate was concentrated and the residue was taken into ethyl acetate, washed with brine and dried over MgS04. Evaporation of solvent provided 20 the title compound as oil (84 mg). RECIEVED IPONZ 22 AUGUST 2011 -356- Step 4: Synthesis of 1-{2-Oxo-2-[4-(4-pyrimidin-2-yl-phenyl)-piperazin-1-yl]-ethyl}-3-propoxy-pyrrolidine-3-carboxyiic acid [3-(4-fluoro-phenyl)-1 H-indazol-5-yl]-amide EtOOC, Synthesis of 1 -{2-Oxo-2-[4-(4-pyrimidin-2-yl-phenyl)-piperazin-1 -yl]-ethyl}-3-propoxy-pyrrolidine-3-carboxylic acid [3-(4-fluoro-phenyl)-1 H-indazol-5-yl]-amide from 3-propoxy-pyrrolidine-3-carboxylic acid ethyl ester was essentially similar to the 10 procedures described above for preparing compounds with a pyrrolidine moiety in the core structure, for example, 1, 3, 60, 85, 98, 128, 183 and 184. Preparation 26 Intermediate To The Synthesis of 3-Morpholin-4-vlmethvl-1-r2-oxo-2-(4-thiophen-15 3-vl-3,6-dihydro-2H-pyridin-1 -vn-ethvn-pyrrolidine-3-carboxvlic acid r3-(2-methvl-pvridin-4-vl)-1H-indazol-5-vn-amide RECIEVED IPONZ 22 AUGUST 2011 -357- Step 1: Synthesis of 2-morpholin-4-vlmethvl-acrvlic acid methyl ester Br o H N 0 COOMe 0 COOMe To a mixture of methyl 2-(bromomethyl)acrylate (119 jil, 1 mmol) and K2C03 (138 mg, 1eq) in acetonitrile (2 ml) was added morpholine (96 |il, 1.1mmols). The mixture was stirred overnight, filtered and concentrated. The residue was partitioned between ether and water, and organic layer was isolated, washed with brine and dried (MgS04). Solvent was removed and residue was purified by column chromatography. Ethyl acetate eluted out the title compound as clear oil (110 mg, 59%). Step 2: Synthesis of 1-benzyl-3-morpholin-4-ylmethyl-pyrrolidine-3-carboxylic acid methyl ester To a stirred cold solution (0 °C) of 2-morpholin-4-ylmethyl-acrylic acid methyl ester (110 mg, 0.594 mmols) and A/-(methoxylmethyl)-A/-(trimethylsilylmethyl)-benzylamine (182 fil, 0.71 mmols) in dichloromethane (2 ml) was added slowly trifluoroacetic acid (9 |il, 0.12 mmols). The resulting solution was allowed to stir at rt overnight and directly purified by column chromatography eluting with ethyl acetate to provide title compound as clear oil (86 mg, 45%). Intermediate To The Synthesis of 1-(2-Oxo-2-r4-(4-pvrimidin-2-vl-phenvl)-piperazin-1 -vn-ethvl}-3-trifluoromethvl-pyrrolidine-3-carboxvlic acid r3-(4-fluoro-phenvP-1 H-indazol-5-vll-amide COOMe Preparation 27 RECIEVED IPONZ 22 AUGUST 2011 10 -358 Si N OMe COOMe CF3 / \ Bn F3C^L_a COOMe N Bn To a stirred cold solution (0 °C) of 2-trifluoromethyl-acrylic acid methyl ester (308 mg, 2 mmol) and A/-(methoxylmethyl)-A/-(trimethylsilylmethyl)benzylamine (529 fxl, 4.8 mmol) in dichloromethane (3 ml) was added slowly trifluoroacetic acid (31 |il). The resulting solution was allowed to stir at rt overnight and directly purified by column chromatography eluting with ethyl acetate in hexane (1:4) to provide 1-benzyl-3-trifluoromethyl-pyrrolidine-3-carboxylic acid methyl ester as oil (438 mg, 76 %). Preparation 28 Preparation of 3-difluoromethyl-pyrrolidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-ethyl ester (2J) & NBoc Jj V^NBoc O 2J 15 3-Formyl-pyrrolidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-ethyl ester 1J (270 mg, 1mmol) was dissolved in CH2CI2 (5 mL) at r.t. followed by addition of DAST (1.0 mL). After 16 hrs, the mixture was cooled to 0 °C and quenched with sat. NaHCC>3 solution followed by extraction of CH2CI2 (2x5 mL). The combined organic layers was dried and concentrated in vacuo. The crude was purified using flash 20 column (eluting with 20% to 33% ethyl acetate in hexanes) to yield 2J (280 mg) as a yellow oil. RECIEVED IPONZ 22 AUGUST 2011 -359- Preparation 29 Preparation of 3-But-2-ynyl-pyrrolidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester 3-But-2-ynyl-pyrrolidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester 5J was prepared essentially similarly as 3-prop-2-ynyl-pyrrolidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester by substituting 3-bromo-propyne with 1-bromo-but-2-yne Preparation 30 Preparation of 3-Methylsulfanyl-pyrrolidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester / °- TMSCH2N2 % ( I. LDA °VV ] - N~Boc o v^n"Boc q ^—^"Boc H0 1K \ 2K Me2S2 °\ 3K Pyrrolidine-1,3-dicarboxylic acid 1-tert-butyl ester (4.3 gm, 20 mmol) was dissolved in 28 mL of toluene and 3.5 ml of methanol. Trimethylsilyldiazomethane 2N solution in hexanes( 13 ml, 26 mmol) was added dropwise at 0 °C and the reaction mixture stirred for 10 min at ambient temperature. The mixture was evaporated to obtain 4.3 gm of oil 2K. To the oil 2K (0.5 gm, 2.1 mmol) dissolved in tetrahydrofuran (15 ml) 1.2 ml of lithium diisopropylamide 2N solution in hexanes was added dropwise and the reaction mixture stirred for 1 hr at -78 °C and let warm to ambient temperature gradually. The reaction mixture was stirred for 18 hrs. A saturated solution of Ammonium chloride (25 ml) was added and the reaction mixture stirred for 5 min. The reaction mixture was extracted with ethyl acetate three times (3x25 ml), dried over magnesium sulfate, filtered and evaporated to give 0.386g of title product 3K. RECIEVED IPONZ 22 AUGUST 2011 -360- Preparation 31 Preparation of 1-Benzvl-3-ethoxv-pvrrolidine-3-carboxvlic acid ethyl ester To a stirred solution of 2-ethoxyacrylate (3 g, 20 mmol) (prepared according to a procedure in Helv. Chem. Acta. 1989, 72, 213-223, the disclosure of which is incorporated herein by reference thereto) and A/-(methoxymethyl)-N-(trimethylsilylmethyl)benzylamine (6.36 ml, 24 mmol) in dichloromethane (30 ml) was added at 0 °C a solution of trifluroacetic acid (0.072 ml, 0.3 mmol) in dichloromethane (2ml). The resulting solution was warmed to room temperature and stirred overnight. The crude product was purified by column chromatography on silica gel eluting with a solution of ethyl acetate in hexane (1:2) to give the title compound 6K (2.1 g, 37%). Preparation 32 Preparation of 1-Benzvl-3-isopropoxv-pyrrolidine-3-carboxvlic acid methyl ester To a stirred solution of 2-/so-propoxymethylacrylate (2 g, 14 mmol) (prepared according to a procedure in Syn. commun. 1977, 7, 43-48, the disclosure of which is incorporated herein by reference thereto) and A/-(methoxymethyl)-N-(trimethylsilylmethyl)benzylamine (4.26 ml, 17 mmol) in dichloromethane (25 ml) was added at 0 °C a solution of trifluroacetic acid (0.2 ml, 3 mmol) in dichloromethane (2ml). The resulting solution was warmed to room temperature and stirred overnight. The crude product was purified by column chromatography on silica gel eluting with a solution of ethyl acetate in hexane (1:2) to give the title compound 8K (1.06 g, 28%). 5K RECIEVED IPONZ 22 AUGUST 2011 -361 - EXAMPLES 338-347 Following procedures similar to those described herein, for example, Examples 1, 3 to 60, 85, 98, 128, 183, 184, the compounds in Table 17 were prepared. "Ex." represents Example. 5 Table 17 Ex. Compound Mass Soec LCMS MH Retention time Minutes 338 ch, n==\ v\xn Q U f 651 2.89 339 ch3 h! /\ ^ v5n 671 2.30 340 ch3 Hi n v-\ ^ YS N^ f 648 3.10 RECIEVED IPONZ 22 AUGUST 2011 -362- 341 ch, n =1 N'^ \=n 674 2.17 342 h,c 3\ XI Q lO f 665 1.42 343 h,c VOu ,cr o (JVch3 ^>0 646 2.19 RECIEVED IPONZ 22 AUGUST 2011 -363- 344 h,c vT" Vdj /X Cy fVch3 ^nT?) \=n x 676 2.31 345 h,c hL Cl, Q U f 649 3.01 RECIEVED IPONZ 22 AUGUST 2011 -364- 346 h,c VOvi H£f* Q q u f 663 3.21 347 h„c 672 3.32 EXAMPLES 348-349 Step 1: Preparation of 2-dimethylaminomethyl-acrylic acid methyl ester Br *2°U3 N(CH3)2 5 1l 2l To a stirred solution of 2-bromomethyl-acrylic acid methyl ester (1 g, 5.59 mmol) in dry CH3CN (20 ml) was added 2M solution of dimethylamine in THF (3.07 ml, 6.14mmol) followed by K2C03 (0.93 g, 6.7 mmol). The reaction mixture was stirred overnight, filtered and washed with CH2CI2. The filtrate was concentrated. The 10 crude product was used in next reaction without further purification. RECIEVED IPONZ 22 AUGUST 2011 -365- Step 2: Preparation of 1-benzyl-3-dimethylaminomethyl-pyrrolidine-3-carboxylic acid methyl ester II r^Ph ^ °VS + TP* ^ N(CHI)2 3L I0CHJ - - 4L To a cold solution of 2-dimethylaminomethyl-acrylic acid methyl ester (0.266 g, 5 1.86 mmol) and A/-(methoxymethyl)-A/-(trimethylsilylmethyl)benzyl-amine (1.43 ml, 5.59 mmol) in dichloromethane (25 ml) was added at 0 °C trifluoroacetic acid (83 fil, 1.12 mmol). The resulting solution was warmed to room temperature and stirred for 72 hours. Saturated aq. NaHC03 (60 ml) was added to the reaction mixture and stirred for 10 minutes. Diluted with dichloromethane (50 ml) and the organic layer was 10 separated. The organic layer was dried over Na2S04, filtered and concentrated. The crude product was purified by column chromatography on silica get eluting with a solution of ethyl acetate in hexanes (1:2) followed by CH2CI2/MeOH/NH4OH (9/1/0.01) to give the title compound (400 mg, 78%). 15 Step 3: Preparation of 3-dimethylaminomethyl-pyrrolidine-3-carboxylic acid methyl ester O 4L O 5L A mixture of 1-benzyl-3-dimethylaminomethyl-pyrrolidine-3-carboxylic acid methyl ester (400 mg),10% Pd/C (40 mg) and methanol (30 ml) was shaken in a 20 hydrogen parr shaker at 45 psi for overnight. The mixture was filtered through celite, washed with ethyl acetate. The combined filtrate was concentrated to give the title compound as oil (260 mg, 96%). 25 Using 5L and following procedures essentially similar to those described herein, for example, Examples 1, 3 to 60, 85, 98, 128, 183, 184, the compounds in Table 18 were prepared. "Ex." represents Example. RECIEVED IPONZ 22 AUGUST 2011 -366-Table 18 EXAMPLES 350-352 5 Following procedures similar to those described herein, for example, Examples 1, 3 to 60, 85, 98, 128, 183, 184, the compounds in Table 19 were prepared. "Ex." represents Example. RECIEVED IPONZ 22 AUGUST 2011 -367-Table 19 Ex Compound Mass spec LCMS MH Retention time (minutes) 350 672 2.38 351 h«SCnJ. hO0UL ^Sr% N'lTY ^ l^N 658 2.43 352 HSO-J^ 0 0 ^Api 658 2.28 RECIEVED IPONZ 22 AUGUST 2011 -368-Preparation 33 Preparation of 3-{[3-(2-Cyclopropyl-pyridin-4-yl)-1 -trityl-1 H-indazol-6-yl]-methyl-carbamoyl}-3-methoxy-pyrrolidine-1 -carboxylic acid tert-butyl ester (4M) NBoc NBoc 3-[3-(2-Cyclopropyl-pyridin-4-yl )-1-trityl-1 H-indazol-6-ylcarbamoyl]-3-methoxy-pyrrolidine-1-carboxylic acid tert-butyl ester 3M (216 mg, 0.3 mmol) was dissolved in THF (10 mL) at r.t. To this solution was added NaH (40 mg, 60% suspension in mineral oil, 1 mmol). After stirring for 10 min, CH3I (0.6 mL, 9.6 mmol) was added. The reaction was worked up after 4 hrs by quenching with sat.NH4CI solution. After extraction with ethyl acetate, the combined organic layers was dried and concentrated in vacuo to obtain 4M. 4M is used as the resulting crude. Preparation 34 Preparation of 2-[6-(3-R-Methyl-piperazin-1 -yl)-pyridin-3-yl]-pyrimidine Br 76 Following essentially the same procedure described in Example 98, Step 7, except substituting an equivalent quantity of 2-R-Methyl piperazine for piperazine the title compound is obtained as a white solid (ESMS MH,256) 95% Yield. RECIEVED IPONZ 22 AUGUST 2011 -369- EXAMPLE 353 Preparation of 3-Ethynyl-1-{2-[2-methyl-4-(5-pyrimidin-2-yl-pyridin-2-yl)-piperazin-1 -yl]-2-oxo-ethyl}-pyrrolidine-3-carboxylic acid [3-(4-fluoro-phenyl)-1 H- indazol-5-yl]-amide Tr Following essentially the same procedure as Example 335, except substituting an equivalent quantity of 2-[6-(3-R-Methyl-piperazin-1-yl)-pyridin-3-yl]-pyrimidine for 23G, the title compound was obtained as a white solid (60%) LCMS (MH, 644.4) Retention time = 2.52 minutes. This racemate was resolved into two single isomers using Chiralpak AD column eluting with 70:30 Hexanes: Isopropanol containing 0.2% Diethylamine. Preparation of 3-(1-Hydroxy-ethyl)-1-{2-oxo-2-[4-(4-pyrimidin-2-yl-phenyl)-piperazin-1 -yl]-ethyl}-pyrrolidine-3-carboxylic acid [3-(4-fluoro-phenyl)-1 H-indazol-5-yI]-amide (1N) (Example 323 in Table 16) F F Isomer A (LCMS) MH 644 Isomer B (LCMS) MH 644 EXAMPLE 354 H N F RECIEVED IPONZ 22 AUGUST 2011 -370- Step 1: Preparation of 3-(1-Acetoxy-ethyi)-1-benzyl-pyrrolidine-3-carboxylic acid methyl ester (2N) \ V*" O , n / TFA/MeCI2 1 ♦ a v —-A O / \ H OMe 2N Trifluoroacetic acid (0.5g,4.38mmol) was added to a solution of methyl-3-5 acetoxy-2-methylenebutyrate (5g, 29.03mmol) and N-methoxymethyl-N-trimethylsilyl benzylamine (6.89g, 29.03mmol) in MeCl2 (50ml) at 0°C then stirred overnight at room temperature. The solvent was evaporated and the residue extracted with EtOAc (200ml) and H2O (50ml) and saturated NaHCOs solution (50ml). The organic layer was separated, dried over MgS04 filtered and evaporated solvent. The residue 10 chromatographed on silica gel eluting with (v:v) EtOAc:hexanes 3:1 yielding compound 2N as a colorless oil (7g, 81.7%)LCMS (MH, 306) Retention time = 2.08 minutes. Step 2: Preparation of 1-Benzyl-3-(1-hydroxy-ethyl)-pyrrolidine-3-carboxylic acid 15 methyl ester (3N) 2M HCI (25ml) was added to a solution of 3-(1-Acetoxy-ethyl)-1-benzyl-pyrrolidine-3-carboxylic acid methyl ester (2N) (5g, 16.39mmol) in MeOH (50ml) at room temperature, then refluxed for 2 hours. The solvent was evaporated yielding the 20 product (4.3g,100%) ESMS (MH,264). RECIEVED IPONZ 22 AUGUST 2011 -371 - Step 3: Preparation of 1-Benzyl-3-(1-hydroxy-ethyl)-pyrrolidine-3-carboxylic acid,Lithium salt (4N) Lithium Hydroxide monohydrate (0.95g,16.37mmol) was added to a solution of 5 1-Benzyl-3-(1-hydroxy-ethyl)-pyrrolidine-3-carboxylic acid methyl ester (3N) ( 4g, 15.20mmol) in MeOH/THF (1/1, 30ml) at room temperature then refluxed for 2 hours. The reaction was cooled and solvent evaporated yielding product (4N) as a solid (4g,100%) ESMS (MH, 250). 10 Step 4: Preparation of 1-Benzyl-3-(1-hydroxy-ethyl)-pyrrolidine-3-carboxylic acid [3-(4-fluoro-phenyl)-1 -trityl-indazol-5-yl]-amide (5N) T rityl. & H XN 4N Li EDCI,HOBT,TEA Trity|, DMF F F Triethylamine (0.5ml, 6.81 mmol), EDCI (200mg, 1.047mmol) HOBT.H2O ( 15 150mg, 1.11 mmol) were added to a solution of the indazole ( 200mg, 0.426mmol) and 1-benzyl-3-(1-hydroxy-ethyl)-pyrrolidine-3-carboxylic acid,Lithium salt (4N) (200mg, 0.803mmol) in DMF (3ml) at room temperature, then stirred overnight at ambient temperature. The solvent was evaporated and the residue chromatographed on silica gel eluting with 1:1 v:v EtOAc: Hexanes yielding product 5N (80mg, 27%) ESMS (MH, 20 701). RECIEVED IPONZ 22 AUGUST 2011 10 -372- Step 5: Preparation of 3-(1-Hydroxy-ethyl)-pyrrolidine-3-carboxylic acid [3-(4-fluoro-phenyl)-1Trityl-indazol-5-yl]-amide (6N) Added ammonium formate (100mg,1.58mmol) to a suspension of 1-Benzyl-3-(1 -hydroxy-ethyl)-pyrrolidine-3-carboxylic acid [3-(4-fluoro-phenyl)-1 -trityl-indazol-5-yl]-amide (5N) (80mg, 0.114mmol) and 10% Pd/C (5mg) in MeOH (5ml) at room temperature then refluxed for 4 hours. The reaction was cooled,diluted with MeOH (20ml) and filtered through a celite pad. The filtrate was concentrated and the residue dissolved in MeCI2 (40ml), dried over MgS04, filtered and solvent evaporated yielding 6N as a solid (60mg, 87%) ESMS (MH, 611). Step 6: Preparation of 3-(1-Hydroxy-ethyl)-1-{2-oxo-2-[4-(4-pyrimidin-2-yl-phenyl)-piperazin-1 -yl]-ethyl}-pyrrolidine-3-carboxylic acid [3-(4-fluoro-phenyl)-1Trityl-indazol-5-yl]-amide (7N) F F OH N H CI"~Y CS2C03/DMF o F RECIEVED IPONZ 22 AUGUST 2011 -373- oh F Added Cesium carbonate (60mg, 0.184mmol) to a solution of 3-(1-Hydroxy-ethyl)-pyrrolidine-3-carboxylic acid [3-(4-fluoro-phenyl)-1Trityl-indazol-5-yl]-amide (6N) 5 (60mg, 0.098mmol)and 2-chloro-1-[4-(4-pyrimidin-2-yl-phenyl)-piperazin-1-yl]-ethanone (50mg,0.158mmol) in DMF (2ml) at room temperature, then stirred overnight. The reaction mixture was diluted with Ether (30ml), insoluble solids filtered, and the solvent was evaporated.The residue was chromatographed on silica gel eluting 10 with 7% MeOH/MeCI2 yielding 7N as a white solid (65mg, 75%) LCMS (MH, 891).Retention time = 4.42 minutes. Step 7: Preparation of 3-(1-Hydroxy-ethyl)-1-{2-oxo-2-[4-(4-pyrimidin-2-yl-phenyl)-piperazin-1 -yl]-ethyl}-pyrrolidine-3-carboxylic acid [3-(4-fluoro-phenyl)-15 1H-indazol-5-yl]-amide (1N) Stirred 3-(1-Hydroxy-ethyl)-1-{2-oxo-2-[4-(4-pyrimidin-2-yl-phenyl)-piperazin-1-yl]-ethyl}-pyrrolidine-3-carboxylic acid [3-(4-fluoro-phenyl)-1 Trityl-indazol-5-yl]-amide (7N) (65mg,0.073mmol) in 85% TFA (2ml) at room temperature overnight. Evaporated 20 solvent. Added EtOAc (50ml) H20 (20ml) 2M NaOH (3ml). Separated organic layer,dried over MgS04, filtered and solvent evaporated yielding a residue which oh 85% tfa h^ 7N ► F RECIEVED IPONZ 22 AUGUST 2011 -374- purified on silica gel eluting with 5% v/v MeOH:EtOAc yielding two diastereomeric racemates. Diastereomer A (20mg,42%) LCMS (MH,649) Retention time = 2.70 minutes Diastereomer B (18mg, 38%)LCMS (MH,649) Retention time = 2.68 minutes. EXAMPLE 355 Step 1: Preparation of 3-(1-Hydroxy-ethyl)-1-{2-[2-methyl-4-(5-pyrimidin-2-yl-pyridin-2-yl)-piperazin-1 -yl]-2-oxo-ethyl}-pyrrolidine-3-carboxylic acid [3-(4-fluoro-phenyl)-1Trityl-indazol-5-yl]-amide (9N) 10 r j o J DMF Added N-N- Diisopropylethylamine (0.3ml, 1.72mmol) to a mixture of 3-(1-15 Hydroxy-ethyl)-pyrrolidine-3-carboxylic acid [3-(4-fluoro-phenyl)-1 Trityl-indazol-5-yl]-amide (6N) (600mg,0.98mmol) and 2-Chloro-1-[2-methyl-4-(5-pyrimidin-2-yl-pyridin-2-yl)-piperazin-1-yl]-ethanone (360mg, 1.15mmol) in DMF (10ml) at room temperature.The solvent was evaporated and the residue extracted with MeCI2 (100ml) and H20 (50ml). The organic layer was separated,washed with saturated 20 NaCI solution (20ml),dried over MgS04, filtered and solvent evaporated yielding 9N as a solid (750mg,84%) ESMS (MH,906). RECIEVED IPONZ 22 AUGUST 2011 -375 Step 2: Preparation of 3-Acetyl-1-{2-[2-methyl-4-(5-pyrimidin-2-yl-pyridin-2-yl)-piperazin-1 -yl]-2-oxo-ethyl}-pyrrolidine-3-carboxylic acid [3-(4-fluoro-phenyl)-1Trityl-indazol-5-yl]-amide (10N) 9N Swern Added DMSO (200mg,2.56mmol) to a solution of oxalyl chloride (180mg,1.40mmol) in MeCI2 (10ml) at -78°C, then stirred at -78°C for 1 hour. Added 3-(1 -Hydroxy-ethyl)-1 -{2-[2-methyl-4-(5-pyrimidin-2-yl-pyridin-2-yl)-piperazin-1 -yl]-2-oxo-ethyl}-pyrrolidine-3-carboxylic acid [3-(4-fluoro-phenyl)-1 Trityl-indazol-5-yl]-amide (9N) in MeCI2 (5ml) at -78°C then stirred at -78°C for 2 hours. Triethylamine (200mg,1.96mmol) was added, the solution allowed warm to room temperature then stirred overnight.Added water (50ml) and MeCI2 (150ml) .The organic layer was separated,dried over MgS04, filtered and solvent evaporated yielding 10N as a solid (600mg,66%) ESMS (MH,904) Step 3: Preparation of 3-Acetyl-1-{2-[2-methyl-4-(5-pyrimidin-2-yl-pyridin-2-yl)-piperazin-1 -yl]-2-oxo-ethyl>-pyrrolidine-3-carboxylic acid [3-(4-fluoro-phenyl)-1 H-indazol-5-yl]-amide (11N) H. 10N TFA Stirred a solution of 3-Acetyl-1-{2-[2-methyl-4-(5-pyrimidin-2-yl-pyridin-2-yl)-piperazin-1-yl]-2-oxo-ethyl}-pyrrolidine-3-carboxylic acid [3-(4-fluoro-phenyl)-1Trityl- RECIEVED IPONZ 22 AUGUST 2011 -376- indazol-5-yl]-amide (10N) (600mg, 0.664mmol) in trifluoroacetic acid (20ml) at room temperature overnight. The solvent was evaporated, water (100ml) and IN NaOH (10ml) were added. The mixture was extracted with MeCh (2x150ml),dried over MgS04,filtered and solvent evaporated yielding a residue which chromatographed on 5 silica gel eluting with 10% v/v MeOH/MeCh containing 2% NH4OH yielding product as a white solid. (350mg, 79%) LCMS (MH 662.4). Retention time (minutes) 2.21 10 EXAMPLE 356 Preparation of 3-(1 -Methoxyimino-ethvO-1 -(2-f2-methyl-4-(5-pyrimidin-2-vl-pvridin-2-vl)-piperazin-1-vn-2-oxo-ethvl>-pvrrolidine-3-carboxvlic acid T3-(4-fluoro-phenyl)-1H-indazol-5-vn-amide (12N) / OMe H2NOCH3 11N TEA/MeOH Added methoxylamine hydrochloride (100mg,1.197mmol) and 15 triethylamine(0.2ml, 1,43mmol) to a solution of 3-Acetyl-1 -{2-[2-methyl-4-(5-pyrimidin-2-yl-pyridin-2-yl)-piperazin-1-yl]-2-oxo-ethyl}-pyrrolidine-3-carboxylic acid [3-(4-fluoro-phenyl)-1H-indazol-5-yl]-amide (11N) (100mg,0.15mmol) in MeOH (5ml),then stirred for 3 hours at room temperature. The solvent was evaporated and the residue was extracted with MeCl2, washed with water,dried over Na2S04, filtered and solvent was 20 evaporated yielding a solid which chromatographed on silica gel eluting with 7%v/v MeOH/MeCh containing 2% NH4OH yielding 2 isomers: (6mg, 6%) (Z)-lsomer LCMS (MH, 691.4) Retention time = 2.45 minutes. (60mg, 63%) (E)-lsomer LCMS (MH, 691.4) Retention time = 2.62 minutes. 25 EXAMPLE 357 RECIEVED IPONZ 22 AUGUST 2011 -377- Preparation of 3-(1-Hydroxyimino-ethyl)-1-{2-[2-methyl-4-(5-pyrimidin-2-yl-pyridin-2-yl)-piperazin-1 -yl]-2-oxo-ethyl}-pyrrolidine-3-carboxylic acid [3-(4-fluoro-phenyl)-1 H-indazol-5-yl]-amide (13N) OH / h2noh 11N TEA/MeOH F Following essentially the same procedure as described in Example 356, except substituting an equivalent amount of hydroxylamine hydrochloride for methoxylamine hydrochloride, the title compound 13N was obtained as a single isomer (E) in 70% yield. (E-lsomer) LCMS ( MH 677) Retention time = 2.44 minutes. EXAMPLE 358 Preparation of 3-[1-(Acetyl-hydrazono)-ethyl]-1 -{2-[2-methyl-4-(5-pyrimidin-2-yl-pyridin-2-yl)-piperazin-1 -yl]-2-oxo-ethyl}-pyrrolidine-3-carboxylic acid [3-(4-fluoro-phenyl)-1 H-indazol-5-yl]-amide (14N) o hn l A h2nnhcoch3 11N MeOH REFLUX F Added acetyl hydrazide (50mg,0.674mmol) to a solution of 3-Acetyl-1-{2-[2-methyl-4-(5-pyrimidin-2-yl-pyridin-2-yl)-piperazin-1-yl]-2-oxo-ethyl}-pyrrolidine-3-carboxylic acid [3-(4-fluoro-phenyl)-1 H-indazol-5-yl]-amide (11N) (50mg, 0.075mmol) RECIEVED IPONZ 22 AUGUST 2011 -378- in MeOH (5ml) at room temperature, then refluxed overnight. The reaction was cooled and solvent evaporated.The residue was extracted with MeCI2 (100ml) and H20 (40ml). The organic layer separated,dried over MgS04,filtered and solvent evaporated.The residue was chromatographed on silica gel eluting with 5% v/v 5 MeOH/MeCb containing 2% NH4OH yielding title compound 14N as a white solid (50mg, 92%) LCMS (MH 718.4) Retention time = 2.13 minutes. EXAMPLE 359 Preparation of 3-Amino-1 -{2-oxo-2-[4-(4-pyrimidin-2-yl-phenyl)-piperazin-1 -yl]-10 ethyl}-pyrrolidine-3-carboxylic acid [3-(4-fluoro-phenyl)-1H-indazol-5-yl]-amide HH2N N o Step 1: Preparation of 3-Amino-3-[3-(4-fluoro-phenyl)-1trityl-indazol-5-ylcarbamoyl]-pyrrolidine-1-carboxylic acid tert-butyl ester (1) O Tiv O HO- J ,—> EDCI/HOBT N/N-B°c TEA/DMF/NMM NH 2 H H2N I \ N. V N—Boc 1P 15 F F Added 3-Amino-pyrrolidine-1,3-dicarboxylicacid-1-tert-butyl ester (86mg, 0.373mmol) to a solution of 3-(4-Fluoro-phenyl)-1H-indazol-5-ylamine (178mg, 0.379mmol); EDCI.HCI (150mg, 0.785mmol) and HOBT (100mg, 0.740mmol) in DMF (2ml) at room temperature. NMM (0.1ml) was added and solution stirred 20 overnight.The solvent was evaporated and the residue extracted with MeCI2 (50ml) washed with H20 (25ml). The organic layer was dried over MgS04 .filtered and RECIEVED IPONZ 22 AUGUST 2011 -379- solvent evaporated yielding a residue which chromatographed on silica gel eluting with 3% v/v MeOH/MeCI2 yielding title compound 1P (185mg, 71%) ESMS (MH 682). Step 2: Preparation of 3-Amino-pyrrolidine-3-carboxylic acid [3-(4-fluoro- phenyl)-1 H-indazol-5-yl]-amide,Hydrochloride (2P) HH2N/ \ HH2N NyX^N-Boc ^ _\ N-H 4M HCI/Dioxane hv ^ N \ N F F 4M HCI/dioxane (2ml) was added to a solution of 3-Amino-3-[3-(4-fluoro-phenyl)-1H-indazol-5-ylcarbamoyl]-pyrrolidine-1-carboxylic acid tert-butyl ester (1P) (60mg, 0.088mmol) in MeCI2 (1ml) at room temperature then stirred for 1 hour at room temperature. The solvent was evaporated. Hexanes (20ml) was added and supernatant decanted.The residue was dried yielding title compound 2P as a white solid (20mg, 69%). ESMS (MH 340). Step 3: Preparation of 3-Amino-1-{2-oxo-2-[4-(4-pyrimidin-2-yl-phenyl)-piperazin-1-y|]-ethyl}-pyrrolidine-3-carboxylic acid [3-(4-fluoro-phenyl)-1H-indazol-5-yl]-amide (3P) o CI-^An^ ^ J 1 M — h _ N [j -1 /I H.. 2P + „ „ N DMF F Added N,N-Diisopropylethylamine (50mg,0.387mmol) to a solution of 3-Amino-pyrrolidine-3-carboxylic acid [3-(4-fluoro-phenyl)-1 H-indazol-5-yl]-amide,Hydrochloride (2P) (15mg, 0.036mmol) in DMF (1ml) and the solution stirred overnight. The solvent was evaporated and the residue extracted with MeCI2 (50ml) and H20 (20ml). The organic layer was separated,dried over MgS04,filtered and evaporated solvent yielding a residue which chromatographed on silica gel eluting with v/v 5% RECIEVED IPONZ 22 AUGUST 2011 -380- MeOH/MeCh containing 2% NH4OH yielding title compound 3P as a white solid (10mg,45%) LCMS (MH 620.3) Retention time = 2.78 minutes EXAMPLE 360 Step 1: Preparation of 3-[3-(4-Fluoro-phenyl)-1Trityl-indazol-5-yIcarbamoyI]-3-formyIamino-pyrrolidine-1-carboxylic acid tert-butyl ester (4P) H H2N /—\ N^N/^N-Boc O MeCI2 + HCOOH CDMT DMAP, NMM CHO H HN N. \ N—Boc O 4P Formic acid (17mg,0.36mmol) was added to a solution of 3-Amino-3-[3-(4-10 fluoro-phenyl)-1trityl-indazol-5-ylcarbamoyl]-pyrrolidine-1 -carboxylic acid tert-butyl ester (1P) 250mg,0.367mmol); 2-Chloro-4,6-dimethoxy-1,3,5-triazine (77mg, 0.44mmol); DMAP (10mg) and NMM (50mg, 0.49mmol) in MeCI2 (3ml) at room temperature.The solvent was evaporated and residue chromatographed on silica gel eluting with 3% v/v MeOH/MeCI2 yielding 4P as a white solid (210mg,80%) ESMS 15 (MH 710). RECIEVED IPONZ 22 AUGUST 2011 -381 - Step 2: Preparation of 3-Formylamino-pyrrolidine-3-carboxylic acid [3-(4-fluoro-phenyl)-1 H-indazol-5-yl]-amide (5P) Tr^ CHO H HN p X N—Boc o 4M HCI/dioxane MeCIo 4P CHO H HN r \ X N-H o HCI 5P 4M HCI (2ml) was added to a solution of 3-[3-(4-Fluoro-phenyl)-1Trityl-indazol-5-ylcarbamoyl]-3-formylamino-pyrrolidine-1-carboxylic acid tert-butyl ester (4P) 0.141 (mmol) in MeCI2 (2ml) at room temperature, then stirred for 1 hour. The solvent was evaporated,hexanes added to residue and supernatant decanted. The residual solid was dried yielding 5P as a white solid (60mg, 100%) LCMS (MH,368.2) Retention time = 1.91 minutes. Step 3: Preparation of 3-Formylamino-1-{2-oxo-2-[4-(4-pyrimidin-2-yl-phenyl)-piperazin-1 -yl]-ethyl}-pyrrolidine-3-carboxylic acid [3-(4-fluoro-phenyl)-1 H-indazol-5-yl]-amide (6P) r 5P + o J DMF CHO H HN I—\ N 6P Added N,N-Diisopropylethylamine (50mg,0.387mmol) to a solution of 3-Formylamino-pyrrolidine-3-carboxylic acid [3-(4-fluoro-phenyl)-1 H-indazol-5-yl]-amide (5P) (60mg, 0.0148mmol) in DMF (2ml) and the solution stirred overnight. The solvent was evaporated and the residue extracted with MeCI2 (50ml) and H20 (20ml). The RECIEVED IPONZ 22 AUGUST 2011 -382- 10 15 organic layer was separated,dried over MgS04,filtered and evaporated solvent yielding a residue which chromatographed on silica gel eluting with v/v 5% MeOH/MeCI2 containing 2% NH4OH yielding title compound 6P as a white solid (60mg, 63%) LCMS (MH 648.4) Retention time = 2.81 minutes. Preparation of 3-Amino-1 -{2-oxo-2-[4-(4-pyrimidin-2-yl-phenyl)-piperazin-1 -yl]-ethyl}-pyrrolidine-3-carboxylic acid [3-(4-fluoro-phenyl)-1 H-indazol-5-yl]-amide (7P) Added 2M HCI (2ml) to a solution of 3-Formylamino-1-{2-oxo-2-[4-(4-pyrimidin-2-yl-phenyl)-piperazin-1 -yl]-ethyl}-pyrrolidine-3-carboxylic acid [3-(4-fluoro-phenyl)-1 H-indazol-5-yl]-amide (6P) (10mg, 0.015mmol) in MeOH (2ml) at room temperature,then stirred for4days at room temperature. The reaction mixture was diluted with Water (20ml),basified with 1N NaOH (3ml) and extracted with MeCh (3x50ml). The organic layers were combined, dried over MgS04, filtered and solvent evaporated yielding 7P as a white solid (7mg, 73%) LCMS (MH 620.3) Retention time = 2.78 minutes. Preparation of 3-Formvlamino-1 -(2-(2-methvl-4-r4-(5-methvl-pvrimidin-2-vn-phenvll-pjperazin-1 -vl>-2-oxo-ethvl)-pvrrolidine-3-carboxvlic acid r3-(4-fluoro-phenvD-1 H-indazol-5-vll-amide (8P) EXAMPLE 361 6P 2M HCI/MeOH EXAMPLE 362 RECIEVED IPONZ 22 AUGUST 2011 -383- CHO 5F F Following essentially the same procedure as described in Step 3 of Example 360 except substituting 2-Chloro-1-[4-(4-pyrimidin-2-yl-phenyl)-piperazin-1-yl]-ethanone with an equivalent quantity of 2-Chloro-1-[2-methyl-4-(4-pyrimidin-2-yl-5 phenyl)-piperazin-1-yl]-ethanone,the title compound 8P was obtained. Chromatography on silica gel eluting with 5% v/v MeOH/MeCh containing 2% NH4OH yields 8P as a white solid (55mg,55%). LCMS (MH 676.4) Retention time = 2.96 minutes. The product is a mixture of 2 Isomers. 10 Analytical column (Chiralpak AD 4.6x250). 40% IPA/Hexanes containing 0.2% DEA: Peak A (isomer A) eluted at 24.501 minutes. LCMS (MH 676.4). Retention time (minutes) 2.96 Compound 8P was separated into single isomers on Chiral HPLC (AD Column) 0 15 Isomer A (9P) Peak B (isomer B) eluted at 33.036 minutes LCMS (MH 676.4) (10P) RECIEVED IPONZ 22 AUGUST 2011 -384- EXAMPLE 363 Preparation of 3-Amino-1 -(2-f2-methvl-4-f4-(5-methvl-pvrimidin-2-vl)-phenvH-piperazin-1 -vl}-2-oxo-ethvD-pyrrolidine-3-carboxvlic acid r3-(4-fluoro-phenvl)-1 H-indazol-5-yll-amide (11P) H. 2M HCI/MeOH 8P ► Following essentially the same procedure as Example 361 except substituting compound 6P with an equivalent quantity of 8P, the title compound 11P was obtained as a mixture of 2 isomers. LCMS (MH 648) Retention time = 2.90 minutes. EXAMPLE 364 CHO H HNI / \ O CH3 A O I 1 9P 2M HCI/MeOH CH3 (12P) RECIEVED IPONZ 22 AUGUST 2011 -385- Following essentially the same procedure as Example 361 except substituting compound 6P with an equivalent quantity of compound 9P (isomer A, Example 372), the title compound 12P was obtained as a single isomer. LCMS (MH 648.4) Retention time = 2.90 minutes. Preparation 35 Step 1: Preparation of S-Pyrimidin^-yl-S'.e'-dihydro^'H-P^'lbipyridinyl-l'-carboxylic acid tert-butyl ester (2Q) PdCI2dppf/dioxane o 10 Refluxed mixture of 2-(6-Bromo-pyridin-3-yl)-pyrimidine (1Q) (200mg, 0.85mmol), N-tert-butoxycarbonyl-1,2,3,6-tetrahydropyridine-4-boronic acid, pinacol ester (290mg, 0.93mmol); Cesium Carbonate (500mg, 1.538mmol); PdCI2dppf (30mg) in dioxane/H20 (10ml v/v 4/1) for 4 hours. Cooled reaction, then evaporated solvent. 15 Extracted with EtOAc (200ml) washed with H20 (50ml), dried over MgS04, filtered and solvent evaporated yielding a solid which chromatographed on silica gel eluting with 30% v/v acetone/hexanes yielding 2Q as a white solid (110mg, 38%) ESMS (MH.339). RECIEVED IPONZ 22 AUGUST 2011 -386- Step 2: Preparation of S-Pyrimidin^-yl-T^'.S'.e'-tetrahydro-p^'lbipyridinyl (3Q) 4M HCI/Dioxane N^N N^N HCI 2Q 3Q Added 4M HCI/dioxane (5ml) to solution of 5-Pyrimidin-2-yl-3,,6,-dihydro-2'H-[2,4']bipyridinyl-1 '-carboxylic acid tert-butyl ester (2Q) (110mg, 0.325mmol) in MeCI2 (5ml) at room temperature, then stirred 4 hours. Evaporated solvent. Added MeCI2 (100ml), H20 (50ml) and 10% NaOH (3ml). The organic layer was separated, dried over MgS04, filtered and solvent evaporated yielding 3Q as a white solid (90mg, 100%) ESMS (MH, 239) LCMS (MH, 239) Retention time = 1.53 minutes. Step 3: Preparation of 2-Chloro-1-(5-pyrimidin-2-yl-3,,6,-dihydro-2'H-[2,4']bipyridinyl-1 '-yl)-ethanone (4Q) ■i ,N + CI (C2H5)3N/MeCl2 CI O Added chloroacetyl chloride (0.35g, 4.39mmol) in MeCI2 (15ml) to a solution of 5-Pyrimidin-2-yl-1 '^'.S'.e'-tetrahydro-^^'lbipyridinyl (3Q) (0.4g, 1.68mmol) and triethylamine (0.4g, 2.87mmol) in MeCI2 (10ml) at 0°C, then stirred 2 hours at O0C. Added saturated NaHC03 solution and stirred an additional hour at 0°C. MeCI2 RECIEVED IPONZ 22 AUGUST 2011 -387- (100ml) was added, organic layer separated, dried over Na2S04, filtered and solvent evaporated yielding 4Q as a pale yellow solid (0.53g, 100%) ESMS (MH 315). Step 1: Preparation of 3-Amino-pyrrolidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester (1T) Added (Trimethylsilyl)-diazomethane (2M in hexanes: 15ml, 30mmol) to a solution of 3-Amino pyrrolidine 1,3 dicarboxylic acid, 1-tert-butyl ester (900mg, 3.9mmol) in MeOH (5ml) at room temperature. Stirred 10 minutes then evaporated solvent yielding 1T as an oil (0.9g,98%). Step 2: Preparation of 3-Formylamino-pyrrolidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester (2T) Added formic acid (200mg,4.34mmol) to solution of 3-Amino-pyrrolidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester (1T) ( 900mg,3.688mmol); 2-Chloro-4,6 dimethoxy-1,3,5-Triazine (CDMT) (800mg,4.556mmol); DMAP (20mg), and NMM (400mg, 4mmol) at room temperature, then stirred overnight. The solvent was evaporated and the residue extracted with MeCI2 (200ml),washed with H20 (50ml), dried over MgS04, filtered and solvent evaporated yielding a solid which chromatographed on silica gel eluting with 5% MeOH/MeCI2 containing 2% NH4OH yielding 2T as a white solid (725mg, 72%) LCMS (MH 273) Retention time = 2.53 minutes. EXAMPLE 365 1T + HCOOH CDMT DMAP NMM RECIEVED IPONZ 22 AUGUST 2011 -388- Step 3: Preparation of 3-(Formyl-methyl-amino)-pyrrolidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester (3T) NaH/THF/DMF CH3I 10 15 Sodium hydride (60% in oil) (10mg, 0.25mmol) was added to a solution of 3-Formylamino-pyrrolidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester (2T) (50mg, 0.183mmol) in THF (3ml). DMF (1 ml) was added and stirred for 1 hour. Methyl iodide (0.1ml, 1.60mmol) was added and the reaction was stirred overnight. The solvent was evaporated and the residue extracted with EtOAc (50ml), washed with H20 (20ml), dried over MgS04, filtered and solvent evaporated yielding a residue which chromatographed on silica gel eluting with 3% MeOH/MeCI2 yielding 3T (50mg, 94%). LCMS (MH 287) Retention time = 2.77 minutes. Step 4: Preparation of 3-(Formyl-methyl-amino)-pyrrolidine-3-carboxylic acid methyl ester ,Hydrochloride.(4T) Added 4M HCI/dioxane (2ml) to a solution of 3-(Formyl-methyl-amino)-pyrrolidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester (3T) (50mg, 0.175mmol) in MeCI2 (2ml) at room temperature then stirred for 1 hour. The solvent was evaporated yielding 4T as a white solid (45mg, 100%) ESMS (MH 187). RECIEVED IPONZ 22 AUGUST 2011 -389- Step 5: Preparation of 3-(Formyl-methyl-amino)-1-{2-oxo-2-[4-(4-pyrimidin-2-yl-phenyl)-3,6-dihydro-2H-pyridin-1 -yl]-ethyl}-pyrrolidine-3-carboxylic acid methyl ester (5T) Added triethylamine (0.3ml, 2.15mmol) to a solution of (3-(Formyl-methyl-amino)-pyrrolidine-3-carboxylic acid methyl ester, Hydrochloride.(4T) (90mg, 0.405mmol) and 2-Chloro-1 -[4-(4-pyrimidin-2-yl-phenyl)-3,6-dihydro-2H-pyridin-1 -yl]-ethanone (140mg, 0.447mmol) in dioxane (5ml) at room temperature, then stirred at 90°C for 5 hours. The reaction was cooled and solvent evaporated yielding a residue which chromatographed on silica gel eluting with 7% MeOH/MeC^ containing 2% NH4OH yielding 5T as a white solid (100mg, 53%) ESMS (MH 464). Step 6: Preparation of S-fFormyl-methyl-aminoM-^-oxo^-l/l-^-pyrimidin^-yl-phenyO-S.e-dihydro^H-pyridin-l-yll-ethyty-pyrrolidine-S-carboxylic acid,Lithium salt (6T) LiOH/Dioxane 5T 1 Added Lithium Hydroxide monohydrate (13mg, 0.22mmol) to a solution of 3-(Formyl-methyl-amino)-1-{2-oxo-2-[4-(4-pyrimidin-2-yl-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-ethyl}-pyrrolidine-3-carboxylic acid methyl ester (5) (100mg, 0.2159mmol) in dioxane (3ml), then stirred 4 hours at room temperature. The solvent was evaporated yielding 6T as a white solid (95mg, 98%) LCMS (MH 450.2) Retention time = 2.15 minutes. RECIEVED IPONZ 22 AUGUST 2011 -390- Step 7: Preparation of 3-(Formyl-methyl-amino)-1-{2-oxo-2-[4-(4-pyrimidin-2-yl-phenyl)-3,6-dihydro-2H-pyridin-1 -yl]-ethyl}-pyrroiidine-3-carboxyiic acid [3-(4-fluoro-phenyl)-1trityl-indazol-5-yl]-amide (7T) CHO Added EDCI.HCI (75mg, 0.39mmol) and HOBT.H2O (50mg, 0.37mmol) to a solution of 3-(4-Fluoro-phenyl)-1trityl-indazol-5-ylamine (110mg, 0.234mmol) and 3-(Formyl-methyl-amino)-1-{2-oxo-2-[4-(4-pyrimidin-2-yl-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-ethyl}-pyrrolidine-3-carboxylic acid,Lithium salt (6T) (95mg, 0.211 mmol) in DMF (2ml) and NMM (0.1ml) at room temperature, then stirred overnight. The solvent was evaporated and residue extracted with MeCI2 (50ml), washed with H20 (20ml), dried over MgSC>4, filtered and solvent evaporated yielding a residue which chromatographed on silica gel eluting with v/v 9:1 EtOAc: Hexanes yielding 7T as a white solid (89mg, 44%) ESMS (MH 901). Step 8: Preparation of 3-(Formyl-methyl-amino)-1-{2-oxo-2-[4-(4-pyrimidin-2-yl-phenyi)-3,6-dihydro-2H-pyridin-1 -yl]-ethyi}-pyrrolidine-3-carboxylic acid [3-(4-fluoro-phenyl)-1 H-indazol-5-yl]-amide (8T) CHO Added 4M HCI/dioxane (2ml) to a solution of 3-(Formyl-methyl-amino)-1-{2-oxo-2-[4-(4-pyrimidin-2-yl-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-ethyl}-pyrrolidine-3- RECIEVED IPONZ 22 AUGUST 2011 -391 - carboxylic acid [3-(4-fluoro-phenyl)-1trityl-indazol-5-yl]-amide (7T) (89mg, 0.098mmol) in MeCI2 (2ml) at room temperature, then stirred for 2 hours. The solvent was evaporated and the residue extracted with MeCI2 (50ml), H20 (25ml) and 3M NaOH (2ml). The organic layer was separated, dried over MgS04, filtered and solvent 5 evaporated yielding a solid. Hexanes (2x50ml) was added and the supernatant decanted. The residual solid was dried yielding 8T as a white solid (55mg,84%) LCMS (MH 659) Retention time = 2.98 minutes. 8T is a mixture of 2 Enantiomers which separate on a chiralpak AD (4.6x250) column eluting with 60:40 Hex:IPA containing 0.2% DEA.Flow rate = 0.9ml/minute 10 Peak A elutes at 29.52 minutes. Peak B elutes at 35.5 minutes. EXAMPLE 366 Preparation of 3-Methvlamino-1 -f2-oxo-2-r4-(4-pyrimidin-2-vl-phenvl)-3.6-15 dihydro-2H-pyridin-1 -vll-ethvl)-pyrrolidine-3-carboxvlic acid r3-(4-fluoro-phenvh-1H-indazol-5-vll-amide (9T) / Added 2M HCI (2ml) to a solution of 3-(Formyl-methyl-amino)-1-{2-oxo-2-[4-(4-pyrimidin-2-yl-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-ethyl}-pyrrolidine-3-carboxylic acid 20 [3-(4-fluoro-phenyl)-1 H-indazol-5-yl]-amide (8T) (11 mg, 0.017mmol) in MeOH (5ml) at room temperature for 4 days. Evaporated solvent Added H20 (20ml), basified with IN NaOH (2ml), and extracted with MeCI2 (50ml). Separated organic layer,dried over MgS04, filtered and evaporated solvent,yielding residue which chromatographed on silica gel eluting with 10% MeCI2/MeOH yielding 9T (5mg) ESMS (MH 631) 25 RECIEVED IPONZ 22 AUGUST 2011 -392- EXAMPLE 367 Preparation of 3-Methoxymethyl-1-{2-oxo-2-[4-(4-pyrimidin-2-yl-phenyl)-3,6-dihydro-2H-pyridin-1 -yl]-ethyl>-pyrrolidine-3-carboxylic acid [3-(4-fluoro-phenyl)-1H-pyrazolo[4,3-b]pyridin-5-yl]-amide o- 0. Step 1: Preparation of 3-bromo-1H-pyrazolo[4,3-b]pyridine ,f 1. h2nnh2 2. NaOH, Br2 1U 0 2U A mixture of 3-fluoro-2-formylpyridine (1.0 g, 8.0 mmol) in 2 mL of anhydrous 10 hydrazine was heated to 110 C and stirred overnight. The reaction was poured to ice water and extracted with ethyl acetate. The combined organic layer was dried and concentrated to give a crude oil (0.5 g), which was subsequently dissolved in 10 mL of NaOH solution (2 N). To this was added bromine (0.6 g, 3.7 mmol) in 5 mL of NaOH solution (2 N) drop-wise. The reaction was stirred at room temperature for 3 hr and 15 quenched by adding NaHS03 (0.06 g), then HCI solution (6 mL, 4 N). A solid was precipitated, filtered and air-dried to give 2U (0.66 g). Step 2: Preparation of 3-(4-Fluoro-phenyl)-1H-pyrazolo[4,3-b]pyridine F——B(0H)2 Na2C03, Pd(PPh3)4 xBr Dioxane/EtOH/H2Q 20 A mixture of 2U (480 mg, 2.45 mmol), Pd(PPh3)4 (141 mg, 0.122 mmol), 4- fluorophenylboronic acid (412 mg, 2.94 mmol) and sodium carbonate solution (2.4 RECIEVED IPONZ 22 AUGUST 2011 -393- mL, 2 M, 4.90 mmol) in 5 mL of dioxane/EtOH/H20 (7:3:2) was microwaved at 150 °C for 10 minutes. The mixture was diluted with water and extracted with ethyl acetate. The combined organic layer was dried, concentrated and purified by column chromatography to give 3U (362 mg). 5 Step 3: Preparation of 3-(4-Fluoro-phenyl)-1 -trityl-1 H-pyrazolo[4,3-b]pyridine 4-oxide Tr / To a solution of 3U (362 mg, 1.46 mmol) in 8 mL of THF was added NaH (96 10 mg, 60%, 2.40 mmol) at 0 °C followed by addition of chlorotriphenylmethane (570 mg, 2.04 mmol). The reaction was stirred at room temperature for 1.5 hr and quenched with ammonium chloride solution. The aqueous layer was extracted with ethyl acetate, dried and concentrated to afford crude adduct. To a solution of the trityl adduct (260 mg, 0.57 mmol) in chloroform was added mCPBA (216 mg, 0.86 mmol). 15 The reaction was heated to reflux for 6 hr, diluted with dichloromethane and washed with water. The organic layer was dried, concentrated and purified by column chromatography to give 4U (169 mg). Step 3: Preparation of 3-(4-Fluorophenyl)-1 -trityl-1 H-pyrazolo[4,3-b]pyridin-5-20 ylamine To a solution of 4U (138 mg, 0.293 mmol) in 2 mL of pyridine was added p-toluenesulfonyl chloride (67 mg, 0.352 mmol). The reaction was stirred at room temperature for 2 hr and the solvent was evaporated. To the crude residue was RECIEVED IPONZ 22 AUGUST 2011 -394- added 3 mL of ethanol amine. The reaction was stirred at room temperature for 2 hr and poured to ice. The yellow solid was collected by filtration and dried under vacuum to afford 5U (117 mg). 5 Step 4: Preparation of 3-(4-Fluorophenyl)-1H-pyrazolo[4,3-b]pyridin-5-ylamine A solution of 5U (112 mg, 0.238 mmol) in 2 mL of TFA/DCM (1:1) was stirred at room temperature for 1 hr and was concentrated. The residue was purified by column chromatography to give 6U (48.1 mg). Step 5: Preparation of 3-Methoxymethyl-1-{2-oxo-2-[4-(4-pyrimidin-2-yl-phenyl)-3,6-dihydro-2H-pyridin-1 -yl]-ethyl}-pyrrolidine-3-carboxylic acid [3-(4-fluoro-phenyl)-1H-pyrazolo[4,3-b]pyridin-5-yl]-amide F—OH pentafluorophenol (61.8 mg, 0.336 mmol) and DMAP (51.3 mg, 0.42 mmol) in DMF was added dicyclohexylcarbodiimide (0.34 mL, 1 M in DCM, 0.336 mmol). The reaction was stirred at room temperature for 4 hr and concentrated. The residue was purified by column chromatography to give the corresponding ester. To a solution of 20 6U (62 mg, 0.364 mmol) in THF at 0 °C was added NaH (16.0 mg, 0.437 mmol) and RECIEVED IPONZ 22 AUGUST 2011 20 -395- stirred at 0 °C for 0.5 h. To this mixture was added the pentafluorophenyl ester and stirred at room temperature for 1.5 hr. The reaction was quenched by adding ammonium chloride solution. The resulting mixture was concentrated and purified by reverse phase HPLC to afford 8U (16.9 mg). Preparation 36 Chiral salt resolution of 3-methoxy-pyrrolidine-3-carboxylic acid methyl ester .. \ Ho /—\ L-tartaric acid MeOOC^/ \._ 2 _ MeOOC^/ V.. MeO />. / ■ / ^NBn —^NH 10%Pd/C M 0 Crystallized out from MeOH MeOH 1V 3 Bar 2V o rvrvr- / \+ 00C C00H MeO H(f OH 10 3V To a solution of compound 1V (660 mg, 2.65 mmols) in MeOH (30 ml) was charged 10% Pd/C (80 mg). The mixture was hydrogenated at 3 bar overnight using standard Parr apparatus, filtered and washed with MeOH several times. To the methanol solution (20 ml) containing 2V (1.32 mmols) was added L-15 tartaric acid (180 mg, 1.2 mmols), and solid was taken into solution by sonication. Solvent was removed under reduced pressure to a residue to which MeOH (3 ml) was added and the solution was allowed to stand at -20C overnight without disturbing. Crystals formed and MeOH was removed by pipette and crystals were rinsed with MeOH twice. Re-crystallization from MeOH gave 200 mg of complex 3V. EXAMPLES 368-383 Following procedures essentially similar to the examples described above, the compounds in Table 20 are prepared. 25 RECIEVED IPONZ 22 AUGUST 2011 -396-Table 20 Ex Compound M+1 Retention time (min) 368 ch II 0 ° °T1 ■&p ^IX a 678.4 3.18 369 //H CT y~\ /=N H3C 566.3 1.8 370 H\\ 0° N\ -Jl n<*V*I ch3 565.3 2.14 RECIEVED IPONZ 22 AUGUST 2011 -397- RECIEVED IPONZ 22 AUGUST 2011 -398- 375 ,ch3 1 / j , 0 A V=n h3c-0 595.3 2.78 376 ch / \ 0 ^af 661.4 3.16 377 //H CT l> xch3 582.4 2.23 378 H\\ nn 1 \<^n ^,0 h3c" 581.3 2.65 RECIEVED IPONZ 22 AUGUST 2011 -399- 379 ch 0 0 Vi ch3 658.4 2.61 380 ch3 III T / ,—, 0 ^/nv>0nvAn^ V=N a 599.3 3.45 381 //H ^yCXA,^ cr L> A f 569.3 2.62 382 ch / \ ° 0 ° Yn vC^ Ti k^F 661.4 3.21 RECIEVED IPONZ 22 AUGUST 2011 -400- EXAMPLES 384-436 Following procedures essentially similar to the examples described above, the compounds in Table 21 are prepared. Table 21 Ex. Compound M+1 Retention time (min) 384 H3C-0 SOs \_v N-s N V " \ N 629.2 2.94 385 H3C\ o NV ° (V4 u \s5N V RECIEVED IPONZ 22 AUGUST 2011 -401 - 386 °y p L JL Nc^/ H3C ^ T \ 1 iV n 598.25 2.67 387 h,c 3 \ N\ yvf \^5n 650.3 3.55 388 H3Cs 0 <V 0 \ / ^ ch, n ^j Vn 389 0—-pu / 3 °vO ° Hry ^ fy_^ch= ^y-n ~N CH3 669 2.34 RECIEVED IPONZ 22 AUGUST 2011 -402- 390 °\ ° TyJ P N^Y h3C ^ y i L 672.34 2.88 391 H3C VYV^ K^>n 392 ° /-—1 0 J==\-n \ Nx"?'"xi rV^ /° N^Y HjC ^ | i CL /\7 690.32 3.26 393 H,C K/-\ L t = 598.4 2.61 RECIEVED IPONZ 22 AUGUST 2011 -403 - 394 h3c WnJ^n^QI. L / 0 N-W Yq 643.4 2.38 395 o / i o ch3 n"\\ f ° i i i r—^ ' h3c ^ 11 1 6^ 0 n \/ ^ 686.35 3.1 396 rf" L J L 1 <Xi Yi HI ^ 0 650.3 3.09 397 H3C 0 P NJ ^ N^n \^n 618.3 2.31 RECIEVED IPONZ 22 AUGUST 2011 -404- 398 h3^ n"\ ff rs iPY™3 ^r% Vn nW h3c 660.4 2.21 399 h3c ^ -y^cv, N\l V^ycha \^n 572.13 2.45 400 Macx 4o, rfN ^ NV u ON 633.3 3.11 401 h,c 3\ " V~\ /\ (V4 Tj \^n ^ 670 2.11 RECIEVED IPONZ 22 AUGUST 2011 -405- 402 /N^ii n O > H C/0 fY O 640 3.1 403 H,C 3\ r\XF ( / F \s^N V 697 3.15 404 /^N N ^ S^Y%\ 689 3.05 405 H3C J^n, Wv-- 672 2.38 RECIEVED IPONZ 22 AUGUST 2011 -406- 406 o rO~N . ?S n 667.28 3.98 407 0 vYi 408 cr^'J o N^y 0 Nn==\ /CH3 Y\X n ] \ ' CH3 N\-^ \^N ^ 409 h,c 3 \ 0Y^vA n \ nv^^v-"\ Jr- s 625.3 3.15 RECIEVED IPONZ 22 AUGUST 2011 -407- 410 hjc rf 0* f 686.2 3.55 411 p ,^o 8 ao /f^ N F 685.2 4 412 XYN yy Cf ^Vs (TY N^ f 697.4 3.85 413 o /~~-i o ch3 rv/ ry-^ '° h3c Y^| Q u f 663.31 3.8 RECIEVED IPONZ 22 AUGUST 2011 -408- 414 ,CH, ? O 0 ° \ o 634.3 3.53 415 Jpcuu fy* i ii \^r AO F 611.4 3.75 416 ^CH, ? „ ° SOJV\ ^ /n~^ ^-A\A /n^ 0 ° Nx N \ \ \ O 636.32 3.46 417 H,C No „ v1 ^ N— /"y F 549.2 3.42 RECIEVED IPONZ 22 AUGUST 2011 -409- 418 F-{ "X" V=N 705.5 3.2 419 ° /—-i 0 H3C ^ HI W^X7 N \/ 686.31 2.64 420 h3C, 0 oC / o ^TV\J( VN NW 689.4 2.47 421 0 oJVN^N \ Ns -J. 576.2 4.3 RECIEVED IPONZ 22 AUGUST 2011 -410- 422 h,c 3 \ /n n-^\ 0 0? " J / 1 n" \ ^ n i \^n 592.3 1.8 423 f^p I J, <2. ^ N]f%] f 685.2 4 424 h,c 3 \ 4qjl /n n"x 0 cu n t /ty N" (VVF IT'S 700.4 2.72 425 h3c NCI N^v^l \^N 618.3 2.25 RECIEVED IPONZ 22 AUGUST 2011 -411 - 426 h3cx °^)On rrN ^ LJ L i XI Y" iQ h3c-° 680.4 3.74 All P 0 N\ I F 574.22 4.06 428 h.c 3 \ P 0 N J f 574.22 4.04 429 kj /t\ 0 o F F Q v-n o 680.4 3.35 RECIEVED IPONZ 22 AUGUST 2011 -412- 430 H3Cn 0 N\ -J. /\ 559.4 2.61 431 1376872 ^ J vJ /° V^/N'A r h3c I / f FQ 0 684.4 2.94 432 1338111 H,c 3 \ 0 N\ xn F 575.2 4.3 433 h3cn ch, 0 | 3 n^/V,n .A. J^n. J\ /ch3 /-(1 W/ CH3 N\ -J. /\ \^N 627.4 2.7 RECIEVED IPONZ 22 AUGUST 2011 -413- 434 h,c 3 \ n J f 586.1 4.2 435 h3cx °&U. fyN r/jf Y% -J 666.4 3.23 436 h3c 0 • 595.3 2.88 EXAMPLES 437-509 Following procedures essentially similar to the examples described above, the compounds in Table 22 are prepared. 5 RECIEVED IPONZ 22 AUGUST 2011 -414 -Table 22 Ex. Compound M+1 Retention time (min) 437 CH3 N J H3C 646.4 1.85 438 h,c—o ^Xx XXN N-^\ NXl F "S)l r iTF \^-N 612.3 2.7 439 N^\ & YS UyVV™1 J iT T T T V-N ° N 0 720.4 2.12 440 CH3 Joaao n Y^y-cH, \=sN 557.3 2.34 RECIEVED IPONZ 22 AUGUST 2011 -415- 441 ?Ha o n 0 ly"! r~( N^S N |l 670.4 4.03 442 1364199 ch, Ir-^ o ch3 /N fy )I N liY 666.4 3.81 443 fH, qyt-j o \ f i 0^ ^Ni]0Y'cl \^N 652.3 3.63 444 ch, / 3 °v—1 0 0=sf o n-_1/ \ \ a ^Xr \^>n 584.3 2.64 RECIEVED IPONZ 22 AUGUST 2011 -416- 445 CH, •fAj 578.3 3.4 446 CH, ^nYS N\yA ir\ \^N 658.4 2.96 447 CH3 0^ 0 0" n. n j ^ir1^ ^i^01 N 664.3 3.55 448 cn3 o^CXAp 676.4 3.27 RECIEVED IPONZ 22 AUGUST 2011 -417- 449 ch3 -sJoju ^ xN [II Jpf AL> N J |yCH 3 \^n 558.2 2.35 450 ch3 £f °r> n J N=\ ly^ yssn 560.3 2.27 451 ch3 N Y ^VS c3 N J f 647.1 3.81 452 n\ f 672.4 3.07 RECIEVED IPONZ 22 AUGUST 2011 -418- 453 ch, / 3 f? CH3 x-—/n l n k^N 658.4 2.88 454 °\ /~~1 ° /Vn o ch3 l jl .n f 561.1 3.67 455 f"3 0sn o o\x h N\k \^n 456 rvV/CU^s tP"v C3 f 649.3 4.09 RECIEVED IPONZ 22 AUGUST 2011 -419- 457 9H» o 458 rv>"Pan CH3 C3 f 459 h3c V / ° ^if^l /l A <K J-1 ^ N l^r U 655 2.11 460 ch3 jCH^OU. N=\ ^J\/N TV5" \s^N 640 2.75 RECIEVED IPONZ 22 AUGUST 2011 -420- 461 1375417 N\J 604.3 2.19 462 CH3 ^cuu. rr ^Vi wl na Y\- CHb \=n 662.2 3.04 463 ch3 4°^ I I 0 N\ 1 A \^n 647.4 3.73 464 CH, /k-/ n t N= \ ^ Y^V-ch3 RECIEVED IPONZ 22 AUGUST 2011 -421 - 465 r=C o V_/ F xch3 1 )N 0-^ n ( ch3 665 2.6 466 ch, jry« vJff tr n V_ V-H A ; VNX V. v f~p s^J> —N j. ^ 615.3 2.24 467 CH3 CXaQ 658 2.28 468 tr\ s 0=^N^Ap n k/NvY^| <ri Nx A II 1 L^k0/cH3 RECIEVED IPONZ 22 AUGUST 2011 -422- 469 ch3 nc5;/s n 7 Ty-0 h3 \s?n 558.1 2.35 470 h3c V / ° /T /N\ 632 3.09 471 ch, •&U /\/n n"** \ & rs (VV ir\ \^N H\J 686.4 2.7 472 ph3 0 n j RECIEVED IPONZ 22 AUGUST 2011 -423- 473 CH, pcij JCT Q-o (^i 657 2.35 474 V^N H3C 592.3 1.82 475 CH3 °\n rvN 0 O, V( XX/S O N 476 ° A—i 0 /V-Nr 0 fAj CH, U " •O 623.3 3.17 RECIEVED IPONZ 22 AUGUST 2011 -424- All H3C^ N" Xs! yN H3C -2.18 2.18 478 O r^o-cH3 ( | J 1 662.4 3.33 479 /CH3 ^■YOOp^ N 11 1 ^ N^J 634 3.09 480 CH, OCX 1 ^ ?H3 J : fY CAN^ <T N (fl N- ^ F CH, 663 3.21 RECIEVED IPONZ 22 AUGUST 2011 -425- 481 CH3 kOJU Ni-/S N 7 V=\^. |yc^ 685.4 4.18 482 /*, rO:°l rp" -OVi b> 483 H3C V ) ° ^if^i N A 1 ^ Nn""W^f Ks 683 2.89 484 - A °\ V~n--A %Jl CH3 N-X / CH, \ 1 F X /"N N O 646.4 3.12 RECIEVED IPONZ 22 AUGUST 2011 -426- 485 ch3 jQf O ^ N TA 650 2.58 486 /NVkl J rVF ° ^ (J CH, \g-\ F O 650.4 2.96 487 °yp»JU 7^~ "xy ^-0 n-^ 488 0^ Cf T^C \^N \^\ A 673 2.63 RECIEVED IPONZ 22 AUGUST 2011 -427- 489 h3c f / 0 /i N IPY ^ v^p 650.4 3.11 490 h,c^ ■vt> t Np-\ '\/s x^n f'l^f f 611.3 3.37 491 ch3 /^Cu, o-f 492 h3c f / ° ^ ^if ^ N Ks 1 ch3 644 2.75 RECIEVED IPONZ 22 AUGUST 2011 -428- 493 ch3 n\ j f 494 chg 0 rrYp-Vi ° 3 1^1 672.4 2.11 495 /ch3 N^a ncx 650 3.47 496 r\-y ch. \--nV\ nY~ X> f 649.3 4.08 RECIEVED IPONZ 22 AUGUST 2011 -429- 497 h3cv N' Xs! )f% VN 675.4 2.46 498 ch, / 3 y~~\ fYN /\ ' N 499 ch3 Ya°Ts n-—/ Q-f 0 / h3c 500 ch3 X^cv. v // ° Y N\X 633 2.73 RECIEVED IPONZ 22 AUGUST 2011 -430- 501 pi3 0 n n% y y 502 \ / ch, n—. N \/F / / (3 \_--n O 689 2.22 503 ch3 °VY 0 0^° O x "■v> ^vs nV n ,-fi 622.2 2.68 504 a v^\J( CHs ) hovy O 673.4 1.79 RECIEVED IPONZ 22 AUGUST 2011 -431 - 505 fix '■». —- N o 506 ch3 0 \ \ A \^N 507 yU^X/N fycH3 ('/ CH3 N-\ F "N^N o 646.4 3.03 508 /nY1 S rV ^ na° <_/ CH3 V~\ F o 664.4 3.02 RECIEVED IPONZ 22 AUGUST 2011 -432- 509 H3Ck 0 -V YS N\^l 687.4 2.34 \<Z-N o EXAMPLES 510-602 Following procedures essentially similar to the examples described above, the compounds in Table 23 are prepared. 5 Table 23 Ex. Compound M+l Retention time (min) 510 H,C 3 \ |j V u 647.3 3.7 511 HC 0-N N J Yy-CH3 \s^N 553 2.42 RECIEVED IPONZ 22 AUGUST 2011 -433- 512 HC\ 0 0 0 NS /WCH3 " 11 1 554 1.88 513 HC\ /ksj 0 "JT i-j N=Y N—' rycH3 \ssN 626 1.9 514 HC /j N=^\ ry0^ 551 2.94 515 HC NV ° ^V^i rvcH- u Xs^N ^ 626 1.9 RECIEVED IPONZ 22 AUGUST 2011 -434- 516 HC\ HkJ I OA rv* \A n^ch3 652 2.19 517 hc xr^V, '"v-, ^v"s (V* u v?n 638 1.84 518 HC\ rr->ao "V 0 V*l Q ^0 641 2.93 519 HC\ .^OJU naJ ° <n=v-x rv^ \ssn v 623 1.97 RECIEVED IPONZ 22 AUGUST 2011 -435- 520 H\\ vCUT Q *0 F 644 2.53 521 HC\ y • ry^ \s=-N 564 1.74 522 I Q * o % o, F 665 3.17 523 HC AX ° N T 11 1 ^ Y-\ kAs/% o o \==N ^ 612 1.97 RECIEVED IPONZ 22 AUGUST 2011 -436- 524 HC. n\ j \^N 630 2.59 525 H.C^CH, ^ VO - Y\ °r- T\ F 663 3.17 526 HC nr^>OJ^ /y 0 Xn=\ xy ro \5=-N ^ 637 2.5 527 Vou. N 1 vN^yYCH3 l^N 701.4 2.64 RECIEVED IPONZ 22 AUGUST 2011 -437- 528 H\\ if V/nvn o u \==n h3c 529 HC\ /kJ 0 n j II 1 \f=-( rvc"- Ij 625 2.57 530 H\\ V°JUC n=( Q U f 644 2.53 531 ^ch2 ^°ao 0 ^Y*i 01 n^l h3c^ 658.4 2.68 RECIEVED IPONZ 22 AUGUST 2011 -438- 532 HC\ <Y 0 vi "~V-\ /\ (V4 u \^n ^ 652 2.26 533 n j \^N 646 2.86 534 hc. NV 0 xx f 629 2.85 535 °CK^ n 1 NN^y^.ch3 626.3 2.87 RECIEVED IPONZ 22 AUGUST 2011 -439- 536 &; t:xO ii i ch3 642.4 2.25 537 hc. U \ 0 a N |TY \^n ch3 572.3 2.06 538 ch, / _ h3c—N j y o fCy Oy. iy-f 539 cP-^Pi h3c oh f *0 649 2.68 RECIEVED IPONZ 22 AUGUST 2011 -440- 540 hc. N\ A. /\ \^n 652 1.98 541 hc /kO o N\=J " /) n=< n-_y f 555 2.7 542 he n | NN=ypy-CH3 \^n 543 rfPi\ S~~\ v ^ 555 1.43 RECIEVED IPONZ 22 AUGUST 2011 -441 - 544 0 0 W^i ch3 652.4 (2.21) 2.21 545 n k-;>n ch3 567.3 546 HC\ n if/ \s^n 562 2.76 547 ^YY'OA" NV 0 WN-, N\P \^N 526 0.82 RECIEVED IPONZ 22 AUGUST 2011 -442- 548 h3c « r 0 Yr^i \=5n h3c 644.4 2.26 549 HC\ 0 ky\^s N\ Y « /> n=\ n—y f 557 2.61 550 tfYcv, or ^YS fl ^ f 646 2.8 551 ch, n—0 h,c-_// ; , 0 Q ° ^ wVi x -iA 676 3.12 RECIEVED IPONZ 22 AUGUST 2011 -443- 552 hc, n n-^^~f Y /ch3 Y*n 643 2.02 553 hgc ^ y^n ch3 571.3 2.55 554 P 'D-v-'S P n A ^ %N 655.4 2.87 555 ch2 t^v, nx Y Y ^ kY-F 649 3.1 RECIEVED IPONZ 22 AUGUST 2011 -444- 556 hc \ n£J o, Trv-cH, ii i // NJr 3 "^N 650 2.57 557 n \^n CHs 571.3 2.16 558 n 5H3 0 "XVs nJ. n^ch3 '"XX 648 3.85 559 h3c i^v ~V ° ■n ^0 \=^n h,c-° 660.4 2.72 RECIEVED IPONZ 22 AUGUST 2011 -445- 560 H\\ voju: ov Xfg=\ q u f 644 2.53 561 HC\ 0 n u Yi (v* ih, 592 1.88 562 hc, °>V? 0 i^p~N 0 0- uf 580 1.94 563 n h! A °A \—7 n 0 ( 674 2.42 RECIEVED IPONZ 22 AUGUST 2011 -446- 564 Ou, NCC 645 3.35 565 ch3 0 ° Aa a n"v^% ii i t j 646 2.8 566 hc rrvca0 % no \ 567 ch, A £T" 1 UL ^vf n^j 646 3.15 RECIEVED IPONZ 22 AUGUST 2011 -447- 568 ch / 3 0 0 ° " ri f 676 3.12 569 ch3 h3c^k{ n <X T1 \/\ f 645 3.34 570 ,ch3 h3c n , y o ch3 JvnYA }X/ 0 \X NAT'S "U "A f 676 3.4 571 "a ci ° ^ yp "YA JCX 686.4 2.57 RECIEVED IPONZ 22 AUGUST 2011 -448- 572 ch, A gy A--s Tl n^j 646 3.17 573 ch3 hoj^-ch3 vo = / \ n // JCY" "A \Y O Q f 681 3.05 574 ch3 1 \ n ° NCf u. ^ 646 2.8 575 ch3 hjsfl j f* nJvnv^a 0 ° ^ or n'\^> ii Jl A n A ch3 f 676 3.35 RECIEVED IPONZ 22 AUGUST 2011 -449- 576 hc. „ V\>«^ ^ /=^N n } f 629 2.72 577 Hc\ AC ° k/n^n^ \Y Y ] f 567 2.61 578 hc. >y^CXX~. nV 0 ^Y*i rv* u \^n v 628 2.27 579 ch3 /\/n n^A~f N\ J f 651 3.48 RECIEVED IPONZ 22 AUGUST 2011 -450 - 580 hc. -n 636 2.69 581 H'/ \ ° A i n a ,n i i n^t Q f 605.4 3.72 582 hc ,3oju ly n] s~^ 575.3 2.98 583 n 1 0"chi 583.3 2.91 RECIEVED IPONZ 22 AUGUST 2011 -451 - 584 O 0 k^n c) ch, 587.3 2.76 585 h3c\ ^ch3 rt-^-cv, N|YA ^10 586 h3c AP ° k/Nv-^ n T T i N=V\ ^V% Q O f 647.4 3.08 587 oh ;fOjy- 1? x, f RECIEVED IPONZ 22 AUGUST 2011 -452- 588 HC\ JyJ o p^ch3 \^n 568 1.96 589 h3c^ /ch3 3 O^Ou, n in ^ 590 /—\ ° iC- U YS n \s=7 f 541 2.18 591 O 0 at ° X)y% lj> 681.2 4.21 RECIEVED IPONZ 22 AUGUST 2011 -453- 592 h3c )rS ^10 \^n h3c0 678.4 2.95 593 n 1 k^n ch3 571.3 2.61 594 h2c=s, n\ 1 h,Xn 567.3 2.1 595 HC\ ~V ° f 629 2.78 RECIEVED IPONZ 22 AUGUST 2011 -454- 596 0T °'rx "An A 655.4 597 rr!rcao "T 0 no \=N 642.4 1.85 598 H3C yy} 6a ^ Q 619.4 3.71 599 CH, rr^ JCX O *T V-S ' Q % F N\^/ 659 2.94 RECIEVED IPONZ 22 AUGUST 2011 -455- 600 .0 #T A) \ -a 647 2.91 601 "A 0 Vi N ij 602 ° XJvs Preparation of 37 Step 1: Preparation of 3-cyano-3-trimethylsilanyloxy-pyrrolidine-1-carboxylic 5 acid ferf-methyl ester /—y TMSCN, KCN TMSO/—\ O^C^NBoc ><^NBoc 1W 18-crown-6 m To a solution of 3-oxo-pyrrolidine-1-carboxylic acid ferf-butyl ester 1W (10 g, 52.3 mmol) in CH2CI2 (150 ml) at 0 "C was added trimethylsilyl cyanide (8.5ml, 63.6 mmol), potassium cyanide (0.34 g, 5.23 mmol) and 18-crown-6 (1.38 g, 5.23 mmol). 10 The reaction mixture was brought to room temperature and stirred overnight. The RECIEVED IPONZ 22 AUGUST 2011 -456- reaction mixture was cooled to 0 "C and quenched wi th saturated NaHC03 (200 ml). The organic layer was separated, dried over Na2S04, filtered and concentrated. The residue was purified on silica gel eluting with 1/8 EtOAc/hexane to give the desired product 2W (2 g, 81%). Step 2: Preparation of 3-hydroxy-pyrrolidine-1,3-dicarboxylic acid 1-ferf-butyl ester 3-methyl ester TMSO /—\ „ H0\/ \ NBoc 1HCI o X^NBoc NC ► / ^ 2W 2. MeOH O 3w A mixture of compound 2W (5.3 g, 25 mmol), MeOH (50 ml), 4N solution of HCI in dioxane (10 ml) was heated in a sealed tube at 70 "C for overnight. The reaction mixture was concentrated and THF (20 ml) was added followed by CH2CI2 (50 ml), triethylamine (16 ml) and di-ferf-butyl dicarbonate (11 g). The reaction mixture was stirred at room temperature for overnight and then concentrated. Diluted the residue with ether (200 ml) and washed with water (100 ml). The organic layer was separated, dried over Na2SC>4, filtered and concentrated. The residue was purified on silica gel eluting with 1/1 EtOAc/hexane then 2/1 EtOAC/hexane to give the desired product 3W (4.35 g, 71%). Step 3: Preparation of 3-(benzo[1,3] dithiol-2-yloxy)-pyrrolidine-1,3-dicarboxylic acid 1-ferf-butyl ester 3-methyl ester To a solution of compound 3W (2.8 g, 11.4 mmol) in CH2CI2 (100 ml) was added 1,3-benzodithiol-2-ylium tetrafluoroborate (5.4 g, 22.8 mmol) followed by pyridine (0.2 ml). The reaction mixture was stirred at room temperature for five days. Quenched the reaction mixture with triethylamine (9.6 ml) and stirred for 15 minutes. The reaction mixture was washed with water (100 ml), dried over Na2S04, filtered and RECIEVED IPONZ 22 AUGUST 2011 -457- concentrated. The residue was purified on silica gel eluting with 1/4 EtOAc/hexane then 1/2 EtOAC/hexane to give the desired product 4W (2.75 g, 61%). Step 4: Preparation of 3-difluoromethoxy-pyrrolidine-1,3-dicarboxyIic acid 1-tert-butyl ester 3-methyl ester o 4W O 5W To a solution of compound 4W (2.45 g, 6.16 mmol) in CH2CI2 (100 ml) at 0 "C was added DAST (3.97 g, 24.64 mmol). After 5 minutes NIS (4.29 g, 18.5 mmol) was added. The reaction mixture was brought to room temperature and stirred for 2 hours. The reaction mixture was then cooled to 0 "C and treated carefully with saturated NaHC03(60 ml) and stirred for 15 minutes. Diluted with CH2CI2 (100 ml) and washed with saturated NaHC03 (2 x 100 ml). The organic was dried over Na2S04, filtered and concentrated. The residue was purified on silica gel eluting with 1/4 EtOAc/hexane desired product 5W (0.45 g, 25%). EXAMPLES 603-605 Following procedures similar to those described herein, for example, Examples 1, 3 to 60, 85, 98, 128, 183, 184, the compounds in Table 24 were prepared from compound 5W. In Table 23 "Ex" represents "Example". RECIEVED IPONZ 22 AUGUST 2011 -458-Table 23 Ex Compound Mass spec LCMS MH Retention time (minutes) 603 V €5 N iPl ^F 668 3.16 604 YF l^s ™ A ^ ^lf *1 N 1^1 NV 670 3.14 605 VF <^X o ^/nY^| hn>X^ ^if^S N iT^l M ^F 671 3.13 RECIEVED IPONZ 22 AUGUST 2011 -459-Preparation of 38 Step 1: Preparation of 4-(4-bromo-2-fluoro-phenyl)-3,6-dihydro-2H-pyridine-1-carboxylic acid ferf-butyl ester °\f Pd(dppf)CI2 6W 7W 5 A mixture of compound 6W (1 g, 3.23 mmol), 4-bromo-2-fluoro-1-iodo-benzene (1.46 g, 4.85 mmol), potassium carbonate (1.4 g, 9.69 mmol), Pd(dppf)CI2 (0.264 g, 0.323 mmol) and 4/1 /dioxane/water (10 ml) was degassed for 15 minutes. Then it was heated at 80 *0 for overnight. Cooled to room temperature and diluted with EtOAc (200 ml). The organic layer was washed with water (100 ml), dried over 10 Na2S04, filtered and concentrated. The residue was purified on silica gel eluting with 1/10 EtOAc/hexane to give the desired product 7W (0.9 g, 78%). Step 2: Preparation of 4-(2-fluoro-4-pyrimid-2-yl-phenyl)-3,6-dihydro-2H pyridine-1-carboxylic acid 1-ferf-butyl ester BocN v \\ /)—Br BocN N=r v_y \ Br~(\ J Kl—J 7W ar—\\ // 8W 15 N- A mixture of compound 7W (0.9 g, 2.53 mmol), bis(pinacolato)diboron (0.96 g, 3.79 mmol), potassium acetate (0.74 g, 7.6 mmol), Pd(dppf)CI2 (0.21 g, 0.25 mmol) and dimethyl sulfoxide (10 ml) was degassed for 10 minutes. Then it was heated at 100 *0 for overnight. The reaction mixture was cool ed to room temperature and 20 potassium carbonate (1.75 g, 12.63 mmol), 2-bromopyrimidine (0.48g, 3.03 mmol) and water (10 ml) were added. The mixture was again purged with nitrogen for 20 min. Palladium tetrakistriphenylphosphine (0.29 g, 0.25 mmol) was added and the reaction mixture was stirred at 100 *0 for a furthe r 2 hr. Cooled to room temperature, filtered through a pad of celite and washed with ethyl acetate. Diluted with water (50 25 ml) and the organic layer was separated. The organic layer was dried over Na2S04, RECIEVED IPONZ 22 AUGUST 2011 -460- filtered and concentrated. The residue was purified on silica gel eluting with 1/5 EtOAc/hexane to give the desired product 8W. Preparation of 39 Step 1: Preparation of 4-(4-bromo-3-fluoro-phenyl)-3,6-dihydro-2H-pyridine-1-carboxylic acid ferf-butyl ester F I—(\ V-Br v><± — -OC> °\f Pd(dppf)CI2 ^ — 6W 9W The compound 9W was prepared from compound 6W using essentially the same procedure as described for the preparation of compound 7W from compound 10 6W. Step 2: Preparation of 4-(3-fluoro-4-pyrimid-2-yl-phenyl)-3,6-dihydro-2Hpyridine- 1-carboxylic acid 1-ferf-butyl ester - / / V-o BocN /)—BocN N=\ 9W Br~(\ 10W N—^ 15 The compound 10W was prepared from compound 9W using essentially the same procedure as described for the preparation of compound 8W from compound 7W but using bis(neopentylglycolato)diboron and 2-bromo-6-fluoro-pyrimidine in place of bis(pinacolato)diboron and 2-bromo-pyrimidine. 20 RECIEVED IPONZ 22 AUGUST 2011 -461 - Preparation 40 Preparation of methyl a, a-dimethoxypropionate OMe O MeO^OMe MeO PMe A + Me0H " ^XOOMe c. H2S04 7 COOMe 5 A procedure similar to Ernest Wenkert, et al. (JACS, 1983, 105, 2021-2029) was followed. A solution of methyl pyruvate (44g), trimethyl orthoformate (62 ml), concentrated H2S04 (0.2 ml) in MeOH (120 ml) was refluxed for 4 hours. In the next one hour period, solvent (about 80 ml) was distilled out. The reaction mixture was cooled to 10 C, poured into a KOH solution (1.2 g KOH in 600 ml water), and 10 extracted with ether (3x). Combined ether extracts were washed with brine and dried (MgS04). After concentration, the residue was distilled under vacuum to provide the acetal (40g, 62%, 40-43C/1 torr). Preparation 41 15 Preparation of 2-methoxyacrylate MeO^OMe TsOH OMe /COOMe ^"COOMe The procedure by Ernest Wenkert, et al. (JACS, 1983, 105, 2021-2029) was followed. To a one neck flask was charged a, a-dimethoxypropionate (150 g) and 20 Tolunesulfonic acid monohydrate (3g) and a short path distillation head was attached. The mixture was heated at 140 C (oil bath temperature) and methanol began to come out first. The product (76 g) was then distilled out later after oil bath temperature was raised over 190C. 25 Preparation 42 Preparation of 1-benzyl-3-methoxy-pyrrolidine-3-carboxylic acid methyl ester -Si^N^OMe + POOMe MeOOCy~, ' L Ph OMe To a stirred solution of methyl 2-methoxyacrylate (20.8 g, 179 mmols) and N-(methoxymethyl)-A/-(trimethylsilylmethyl)benzylamine (55 ml, 215 mmols) in RECIEVED IPONZ 22 AUGUST 2011 -462- dichloromethane (160 ml) was added at 0 C a solution of trifluoroacetic acid (2ml) in dichloromethane (10 ml). The resulting solution was warmed to room temperature and stirred overnight. After concentration, the crude product was purified by column chromatography on silica gel eluting with a solution of ethyl acetate/hexanes/Et3N 5 (1000:3000:4 to 1000:1000:3) to give the title compound (17.7 mg, 40 %). Preparation 43 Preparation of 3-methoxy-pyrrolidine-3-carboxylic acid methyl ester tartaric acid salt Me00C>O, Me00C>O, MeSO, tartaric acid 10 MeOX-N-Ph MeCt~" H Meo2c^V'N'H 2.49 gm of 1-benzyl-3-methoxy-pyrrolidine-3-carboxylic acid methyl ester was hydrogenated in ethanol using 10% Pd/C at 55 psi hydrogen for 24 hrs. Filtration of the Pd/C followed by evaporation of the ethanol 1.6 gm of crude de-benzylated product. The crude product was dissolved in 95 ml of methanol and 1.35 gm of L-15 tartaric acid added. After 24 hrs, the crystals were filtered and re-crystallized from methanol to give 13. 4 grams of title product. EXAMPLES 606-608 Following procedures similar to those described herein, for example, 20 Preparations 38 to 43, and Examples 1, 3 to 60, 85, 98, 128, 183, 184, the compounds in Table 25 were prepared. In Table 25 "Ex" represents "Example". RECIEVED IPONZ 22 AUGUST 2011 -463-Table 25 Ex Compound Mass spec LCMS MH Retention time (minutes) 606 ft ° vAyS HN-C^ 650 3.28 607 HSC>J*-S Qll hnqA\A N'1P*1 ^ 687 2.55 608 0 ^Sr^rF HN, A ^if *] N 638 3.33 RECIEVED IPONZ 22 AUGUST 2011 -464 -Preparation 44 Preparation of 3-(2-ethvlamino-pvridin-4-vl)-1-tritvl-1H-indazol-5-vlamine NH2 Step 1: Preparation of 3-(2-fluoro-pyridin~4-yl)-5-nitro-1 -trityl-1 H-indazole B(OH)2 N02 N02 Ph Ph 'h"> Ph N' N' 1Y 2Y A mixture of 3-bromo-5-nitro-1-trytyl-1 H-indazole (200 mg, 0.41 mmol), 2-fluoro-4-pyridine boronic acid (76 mg, 0.54 mmol), K3P04 (174 mg, 0.82 mmol), Pd(dppf)CI2 (34 mg, 0.041 mmol) and 4/1 /dioxane/H20 (10 mL) was stirred at 100 "C for 18 hours. Cooled to room temperature, poured into EtOAc (200 mL) and washed with water (100 mL). The organic layer was dried over Na2S04, filtered and concentrated. The crude product was purified by column chromatography on silica get eluting with a solution of 15% ethyl acetate in hexane to give the title compound (90 mg, 44%). Step 2: Preparation of ethyl-[4-(5-nitro-1-trityl-1 H-indazol-3-yl)-pyridin-2-yl]-amine N02 N02 W A EtNH2/THF Ph' N" " Ph' N' ■ N 3Y A mixture of 3-(2-fluoro-pyridin-4-yl)-5-nitro-1-trityl-1 H-indazole (800 mg, 1.6 mmol) and 2M ethyl amine in THF (20 mL) was heated in a sealed tube at 80 "C for four days. Cooled to room temperature and concentrated. The crude product was RECIEVED IPONZ 22 AUGUST 2011 -465- purified by column chromatography on silica get eluting with a solution of ethyl acetate in hexane (1:1) to give the title compound (300 mg, 36%). Step 3: Preparation of 3-(2-ethylamino-pyridin-4-yl)-1-trityl-1 H-indazol-5-ylamine A mixture of ethyl-[4-(5-nitro-1-trityl-1 H-indazol-3-yl)-pyridin-2-yl]-amine (30 mg), 10% Pd/C (25 mg) and MeOH (15 mL) was stirred at room temperature under hydrogen atmosphere for 4 hours. Filtered the catalyst, washed with MeOH and concentrated to give the title compound 4 (26 mg) which was used in the next reaction without further purification. Preparation 45 Preparation of 3-(2-methvlamino-pvridin-4-vl)-1-tritvl-1H-indazol-5-vlamine NH2 3-(2-methylamino-pyridin-4-yl)-1 -trityl-1 H-indazol-5-ylamine was prepared following essentially the same procedure as in Preparation 44, except that methylamine is used in Step 2 instead of ethylamine. Following procedures similar to those described herein, for example, Preparations 44 and 45, and Examples 1, 3 to 60, 85, 98, 128, 183, 184, the compounds in Table 26 were prepared. In the preparation of the compound of Example 612, cyclopropylamine is used instead of ethylamine in Step 2 of Preparation 44. In Table 26 "Ex" represents "Example". N02 NH2 4y EXAMPLES 609-613 RECIEVED IPONZ 22 AUGUST 2011 -466-Table 26 Ex Compound 609 h3c vw-- ^ 610 ch3 C/ 0 Nq Kl ^V% EXAMPLE 611 RECIEVED IPONZ 22 AUGUST 2011 -467 Step 1: N02 Step 1. Pt02, EtOAc H2 (balloon) r.t. HO t 1Z 2Z1 N 2Z2 To a solution of compound 1 (510mg, 1.06mmol) in ethyl acetate (15ml), platinum oxide on charcoal (825mg, 0.011 mmol, 5%Pt, 50% wet) was added. The mixture was stirred under hydrogen (balloon) at r.t. until starting material disappeared. The mixture was filtered through Celite and solvents were removed in vacuum to give a mixture of compound 2Z1 and compound 2Z2. The mixture was used in the next step without further purification. Step 2: 2Z1 + Step 2. HATU, pyridine DMF, r.t. CNBoc H 3Z O H I NBoc N""lf O 4Z1 The mixture from step 1 was dissolved in N, N-dimethylformamide (10ml), HATU (484mg, 1.27mmol), compound 3Z (274mg, 1.27mmol) followed by pyridine (0.11 ml, 1,27mmol) were added. The mixture was stirred at r.t. overnight. Water and ethyl acetate were added and layers were separated. The organic layer was washed with water (X2), dried (MgS04), filtered and solvents were removed in vacuum. Chromatographic purification [hexanes - acetone, 4:1 (v/v)] gave less polar compound 4Z2 (241 mg, 35%) as yellow oil. Continuous elution with the same solvent system gave more polar compound 4Z1 (161mg, 23%) also as yellow oil. RECIEVED IPONZ 22 AUGUST 2011 -468- Step 3: HO CNBoc ^ „ Step 3. NBoc MeO N_vs\l 0 NBoc Ph Ph NaH, Mel DMF, r.t. ph Ph Ph 4Z1 To a suspension of sodium hydride (14mg, 0.34mmol, 60% in oil) in N, N-dimethylforamide (5ml) at 0 °C, a solution of compound 4A (152mg, 0.23mmol) in N, N-dimethylforamide (2ml) was added. The mixture was stirred at 0 °C for 20 min and methyl iodide (21jiL, 0.34mmol) was added. The mixture was warmed to r.t. and was quenched with saturated ammonium chloride solution. Water and ethyl acetate were added and layers were separated. The organic layer was dried (MgS04), filtered and solvents were removed in vacuum. Chromatographic purification [hexanes - ethyl acetate, 1:1 (v/v)] gave compound 5Z (23mg, 15%) as yellow oil. Compound 5Z (15mg, 0.022mmol) was stirred in a mixture of dichloromethane (3 ml) and trifluoroacetic acid (1 ml) at r.t. for 5 hr. Solvents were removed in vacuum. Chromatographic purification [methanol (7N ammonia) - dichloromethane, 1:4 (v/v)] gave compound 6Z as yellow oil (3.5mg, 30%). Step 4: Step 4. RECIEVED IPONZ 22 AUGUST 2011 -469- Step 5: o. Step5. O. n=\ CI ^ /jT^, // 6Z 7Z N HN iPr2NEt, DMF, r.t. r^,. // A mixture of compound 6Z (3.5mg, O.OIOmmol), compound 7Z (3.9mg, 5 0.012mmol) and diisopropylethylamine (4|xL, 0.021 mmol) in N, N-dimethylforamide (0.5ml) was stirred at r.t. overnight. Water and ethyl acetate were added and layers were separated. The organic layer was washed with water (X2), dried (MgSCU), filtered and solvents were removed in vacuum. Chromatographic purification [methanol (7N ammonia) - dichloromethane, 1:9 (v/v)] gave title compound as yellow 10 oil (2 mg, 31%). LCMS MH+= 615 (RT = 2.27 min). ASSAYS Coupled ERK2 Assay: Activity of compounds against inactive ERK2 was tested in a coupled 15 MEK1/ERK2 IMAP assay as follows: Compounds were diluted to 25x final test concentration in 100% DMSO. 14pl of kinase buffer (10mM Tris.HCI pH 7.2, 10mM MgCh, 0.01% Tween-20, 1mM DTT) containing 0.4ng unphosphorylated Mouse ERK2 protein was added to each well of a black 384-well assay plate. 1 pi of 25x compound was added to each well and incubated at room temperature for 30 minutes 20 to allow an opportunity for the compound to bind to the inactive enzyme. DMSO concentration during initial incubation is 6.7%. ERK2 activity was determined to be insensitive to DMSO concentrations up to 20%. ERK2 was then activated and it's kinase activity measured by the addition of 10pl kinase buffer with the following components (final concentration per reaction): 2ng active (phosphorylated) human 25 MEK1 protein and 4pM (total) ERK2 IMAP substrate peptides (3.9pM unlabeled IPTTPITTTYFFFK-CONH2 and 100nM IPTTPITTTYFFFK(5-carboxyfluorescein)-CONH2) and 30pM ATP. DMSO concentration during ERK activation was 4%. After one hour, reactions were terminated by addition of 60pl IMAP detections beads in RECIEVED IPONZ 22 AUGUST 2011 -470- binding buffer (Molecular Devices). Binding was allowed to equilibrate for 30 minutes before reading the plate on an LJL Analyst Fluorescence Polarization plate reader. Compound inhibition was calculated relative to DMSO and fully inhibited standards. Active compounds were reconfirmed in an independent assay. 5 Active ERK2 Assay: Activated ERK2 activity was also determined in the IMAP assay format using the procedure outlined above. 1 jj! of 25x compound was added to 14[jl of kinase buffer containing 0.25ng fully phosphorylated, active Mouse ERK2 protein. Following 10 a 30 minute incubation, the reactions were initiated by addition of 1 OjjI of kinase buffer containing 1|jM ERK2 IMAP substrate peptide (0.9|jM unlabeled IPTTPITTTYFFFK-CONH2 and 100nM IPTTPITTTYFFFK(5-carboxyfluorescein)-CONH2) and 30[jM ATP. Reactions proceeded for 30 minutes before termination by addition of 60|jI IMAP detection beads in binding buffer. Plates were read as above 15 after 30 minute binding equilibration. Active compounds were reconfirmed in an independent assay. Soft Agar Assay: Anchorage-independent growth is a characteristic of tumorigenic cell lines. 20 Human tumor cells can be suspended in growth medium containing 0.3% agarose and an indicated concentration of a farnesyl transferase inhibitor. The solution can be overlayed onto growth medium solidified with 0.6% agarose containing the same concentration of ERK1 and ERK2 inhibitor as the top layer. After the top layer is solidified, plates can be incubated for 10-16 days at 37"C under 5% CO 2 to allow 25 colony outgrowth. After incubation, the colonies can be stained by overlaying the agar with a solution of MTT (3-[4,5-dimethyl-thiazol-2-yl]-2,5-diphenyltetrazolium bromide, Thiazolyl blue) (1 mg/mL in PBS). Colonies can be counted and the ICso's can be determined. 30 RECIEVED IPONZ 22 AUGUST 2011 -471 - The AUC (area under the concentration-time curve during the first 6 hours (AUCfihr) in Table 27 below was determined using the Protocol of Cassette Accelerating Rapid Rat screen (CARRS) Animal dosing and sample collection 5 Male Sprague-Dawley rats (Charles River, Co.) were pre-cannulated (femoral artery) in order to facilitate precise blood sampling times, and to reduce the stress on the animals caused by serial bleedings. Following an overnight fast, two rats were dosed orally with one compound at a dose of 10 mg/kg in a 5-mL/kg dose volume. Blood was collected into heparin-containing tubes serially from each animal at 0.5, 1, 10 2, 3, 4 and 6 h post-dosing and centrifuged to generate plasma. Approximately 100 [jL of plasma were collected at the individual time points. The plasma samples were stored at -20 "C until analysis. Plasma sample and standard curve preparation 15 A set of 12 rat plasma samples was generated for each NCE (i.e. 6 timepoints and n = 2 rats). These 12 samples were pooled across the two rats at each timepoint to provide 6 pooled samples (one sample per time point) for each NCE. The pooled samples were assayed as cassettes of six (36 samples total) to provide data on the six compounds. The50-|jL aliquots of the 36 plasma samples were placed into 20 individual wells of a 96-well plate. An additional compound (often a structural analog of the test compounds) was selected as the internal standard. A mini-calibration curve was prepared (three points plus a zero) for each compound assayed. Drug-free rat plasma was measured into 1-mL aliquots and each aliquot was spiked with known concentrations of the compounds to generate standards of the desired 25 concentrations. The concentrations of the standards were chosen to bracket the expected concentration of the pooled samples based on historical data from previous studies on other compounds. For this work, the standards were set to contain concentrations of 25, 250 and 2500 ng NCE/mL plasma. The plasma standards were precipitated in duplicate along with the samples. Protein precipitation occurred after 30 addition of 150 |jL of acetonitrile containing the internal standard at a concentration of 1 ng/mL into each sample well using the Tomtec Quadra 96 system. The precipitated samples and standards were vortexed and centrifuged in the 96-well plate. Approximately 50-100 [jL of the supernatant were removed and placed into a fresh 96-well plate using the Tomtec Quadra 96 system. A volume of 5-10 |jL of the RECIEVED IPONZ 22 AUGUST 2011 -472- supernatant was used for analysis by HPLC-MS/MS. The mini-standard curve was run in duplicate, once before and once after the samples. Thus, a total of 14 study samples plus standards were analyzed per compound. In addition, solvent blanks were injected before and after each set of 14 and after the highest calibration 5 standard for each compound; therefore, a total of 103 injections were made into each HPLC system for each set of six compounds. Multiple solvent blank injections could be made from a single well. Twelve solvent blank wells were designated in each 96-well plate. Thus, one batch (cassette) of six NCEs was prepared and assayed using one 96-well plate format. 10 HPLC-MS/MS analysis All the compounds were analyzed using selected reaction monitoring (SRM) methods with LC/MS/MS instruments. Once the method development had been completed, the assay was quickly set up using a standard injection sequence 15 template for the CARRS assay. The final compounds of Examples 1, 2, 4-61, 65-73, 77-84, 86, 88-98, 100, 102-114, 116-118, 120, 121, 124, 125, 151-155, 159-179, 183, 184, 186, 188-193, 196-199, 202-205, 250, 253-259, 260-299, 301-318, 320-323, 332-347, 356 (Isomer 20 Z), 356 (Isomer E), 357-360, 362, 362 (compound 9P), 364, 368-436, 440-509, 511-602, 606, 607 and 609-611 had an AERK2 IC50 in the range of 0.16 to 20,000 nM. The final compounds of Examples 1, 2, 4-28, 61, 86, 88, 89, 92, 95, 98, 100, 120, 125, 132, 142, 152, 154, 168, 176, 183, 184, 186, 188-193, 196-199, 202-205, 250, 251, 253-259, 261, 264, 269, 271, 274-276, 282, 286, 289, 290, 292, 294, 302, 25 303, 304, 306, 314-316, 332, 333, 335, 338, 343, 358, 362, 368-370, 384-390, 440-493, 510-558, 606, and 611 had an AERK2 IC50 in the range of 0.16 to 18 nM. The final compounds of Examples 6, 100, 183, 184, 186, 188-192, 261, 440-450, and 510-517 had an AERK2 IC50 in the range of 0.16 to 1.5 nM. The final compound of Example 183 had an AERK2 IC50 of 0.16 nM. The final 30 compound of Example 186 had an AERK2 IC50 of 0.78 nM. The final compound of Example 335 had an AERK2 IC50 of 4.9 nM. Table 27 provides AERK2 IC50 data and Rat Auc data for compounds of this invention. RECIEVED IPONZ 22 AUGUST 2011 -473-Table 27 Ex. Compound AERK2 IC50 (nM) Rat AUC PO (nM.h) 336 h3c "Vr U \^N 18.1 7219 469 0"^"JrjTl n A ^ l^r 2.5 1200 480 :^cu N x\ IJ 4.8 1880 489 /CH3 N 11 1 if 1 ^Af 9.1 723 RECIEVED IPONZ 22 AUGUST 2011 -474- 571 H\\ yoju-J¥ Q 0 f 19.5 6466 413 H,C 3\ <1 1 F N\^ 37.6 8946 412 I (VN^° VJ HC/° ,N-"\ o 38.45 7836 462 ^ 0 oXXAo "OY N\ J f 2.1 352 487 8.2 38 RECIEVED IPONZ 22 AUGUST 2011 -475- H,CL 'X "Xs! "''S yN H3C 6 r0^v^'^,0,~0-0 ^ \ Q N N 0.8 0 For preparing pharmaceutical compositions from the compounds described by this invention, inert, pharmaceutically acceptable carriers can be either solid or liquid. Solid form preparations include powders, tablets, dispersible granules, capsules, cachets and suppositories. The powders and tablets may be comprised of from about 5 to about 95 percent active ingredient. Suitable solid carriers are known in the art, e.g. magnesium carbonate, magnesium stearate, talc, sugar or lactose. Tablets, powders, cachets and capsules can be used as solid dosage forms suitable for oral administration. Examples of pharmaceutically acceptable carriers and methods of manufacture for various compositions may be found in A. Gennaro (ed.), Remington: The Science and Practice of Pharmacy, 20th Edition, (2000), Lippincott Williams & Wilkins, Baltimore, MD. Liquid form preparations include solutions, suspensions and emulsions. As an example may be mentioned water or water-propylene glycol solutions for parenteral injection or addition of sweeteners and opacifiers for oral solutions, suspensions and emulsions. Liquid form preparations may also include solutions for intranasal administration. Aerosol preparations suitable for inhalation may include solutions and solids in powder form, which may be in combination with a pharmaceutically acceptable carrier, such as an inert compressed gas, e.g. nitrogen. RECIEVED IPONZ 22 AUGUST 2011 -476- Also included are solid form preparations which are intended to be converted, shortly before use, to liquid form preparations for either oral or parenteral administration. Such liquid forms include solutions, suspensions and emulsions. The compounds of the invention may also be deliverable transdermally. The transdermal compositions can take the form of creams, lotions, aerosols and/or emulsions and can be included in a transdermal patch of the matrix or reservoir type as are conventional in the art for this purpose. Preferably the compound is administered orally. Preferably, the pharmaceutical preparation is in a unit dosage form. In such form, the preparations subdivided into suitably sized unit doses containing appropriate quantities of the active component, e.g., an effective amount to achieve the desired purpose. The quantity of active compound in a unit dose of preparation may be varied or adjusted from about 0.01 mg to about 1000 mg, preferably from about 0.01 mg to about 750 mg, more preferably from about 0.01 mg to about 500 mg, and most preferably from about 0.01 mg to about 250 mg according to the particular application. The actual dosage employed may be varied depending upon the requirements of the patient and the severity of the condition being treated. Determination of the proper dosage regimen for a particular situation is within the skill in the art. For convenience, the total daily dosage may be divided and administered in portions during the day as required. The amount and frequency of administration of the compounds of the invention and/or the pharmaceutically acceptable salts thereof will be regulated according to the judgment of the attending clinician considering such factors as age, condition and size of the patient as well as severity of the symptoms being treated. A typical recommended daily dosage regimen for oral administration can range from about 0.04 mg/day to about 4000 mg/day, in two to four divided doses. While the present invention has been described in conjunction with the specific embodiments set forth above, many alternatives, modifications and variations thereof will be apparent to those of ordinary skill in the art. All such alternatives, modifications and variations are intended to fall within the spirit and scope of the present invention. In this specification where reference has been made to patent specifications, other external documents, or other sources of information, this is generally for the purpose of providing a context for discussing the features of the invention. Unless </div>

Claims

<div class="application article clearfix printTableText" id="claims"> RECIEVED IPONZ 22 AUGUST 2011 -477- specifically stated otherwise, reference to such external documents is not to be construed as an admission that such documents, or such sources of information, in any jurisdiction, are prior art, or form part of the common general knowledge in the art. In the description in this specification reference may be made to subject matter 5 that is not within the scope of the claims of the current application. That subject matter should be readily identifiable by a person skilled in the art and may assist in putting into practice the invention as defined in the claims of this application. The term "comprising" as used in this specification means "consisting at least in part of. When interpreting each statement in this specification that includes the term 10 "comprising", features other than that or those prefaced by the term may also be present. Related terms such as "comprise" and "comprises" are to be interpreted in the same manner. RECIEVED IPONZ 22 AUGUST 2011 -478- WHAT IS CLAIMED IS: 1. A compound of formula 1.0: r8 (1.0) 10 or the pharmaceutically acceptable salts thereof, wherein: Y1, Y2, and Y3 are each independently selected from the group consisting of: -CH=, -N= and -CR9=; z is 1 to 3; Q is a substituent selected from the group consisting of: r6 \ n r4 R4 (2.1) (2.4) r4 15 (2.9) (2.10) (2.11) RECIEVED IPONZ 22 AUGUST 2011 -479- (2.13) (2.14) (2.15) <r K' K' ;>4 r4 (2.17) r5 r5a r6 -r6 -r5 >5A (2.18) (2.20) (2.21) 5A (2.22) Each Q represents a ring independently selected from the group consisting of: cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl, wherein said substituted rings 10 are substituted with 1 to 3 substituents independently selected from the group consisting of: the R10 moieties; provided that when Q1 is aryl, heteroaryl, substituted aryl or substituted heteroaryl then the carbon atoms at the ring junction are not substituted; Q2 represents a ring selected from the group consisting of: cycloalkyl, 15 substituted cycloalkyl, heterocycloalkyl, and substituted heterocycloalkyl, wherein said substituted rings are substituted with 1 to 3 substituents independently selected from 10 the group consisting of: the R moieties; Z1 represents -(C(R24)2)W- wherein each R24 is independently selected from the group consisting of: H, alkyl and F, and wherein w is 1, 2 or 3; 20 Z2 is selected from the group consisting of: -N(R44)-, -O- and -C(R46)2-; m is 1 to 6; RECIEVED IPONZ 22 AUGUST 2011 -480- n is 1 to 6; p is 0 to 6; t is 0, 1, or 2; R1 is selected from the group consisting of: (1)-CN, (2) -N02> (3) -OR10, (4) -SR10, (5) -N(R10)2, (6) R10, (7) -C(0)R1°, (8) -(C(R30)2)n-NR32-C(O)-R10, (9) -(C(R30)2)n-NR32-S(O)t-R10, (10) -(C(R30)2)n-NR32-C(O)-N(R32)-R10, (11) (12) -CF3, (13) -C(0)0R1°, (14) -(C(R30)2)nR13 wherein n is 1, each R30 is H, and R13 is selected from the group consisting of: -OH and -N(R10)2, wherein each R10 is independently selected, 0 wherein each R10 is independently selected, 0 (15) alkenyl, (16) -NR32-C(0)-R14, (17) (18) RECIEVED IPONZ 22 AUGUST 2011 -481 - wherein each R10 is independently selected, (19) NH -C-N-R15 R32 , (20) -C(O)-NR32-(C(R30)2)p-OR10, 5 (21) -C(O)N(R10)2 wherein each R10 is independently selected, (22) -C(0)-NR32-C(R18)3 wherein each R18 is independently selected from the group consisting of: R10 and -C(0)0R19, and R19 is selected from the group consisting of: alkyl and substituted arylalkyl, (23) -C(O)-NR32-(C(R30)2)n-C(O)-N(R10)2, 10 (24) heterocycloalkenyl, (25) % o—' , and (26) arylalkenyl-; R2 is selected from the group consisting of: 15 (1) H, (2) -CN, (3) halo, (4) alkyl, (5) substituted alkyl wherein said substituted alkyl is substituted with 1 to 3 20 substitutents selected from the group consisting of: (a) -OH, (b) -O-alkyl, (c) -O-alkyl substituted with 1 to 3 F atoms, and (d) -N(R40)2 wherein each R40 is independently selected from the group consisting of: (i) H, (ii) C1-C3 alkyl, (iii) -CF3, and (e) halo, (6) alkynyl, (7) alkenyl, 25 (8)-(CH2)mR11, (9) -N(R26)2, (10)-OR23, (11)-N(R26)C(0)R42, (12) cycloalkyl, RECIEVED IPONZ 22 AUGUST 2011 -482- (13) cycloalkylalkyl, (14) ^(C(R30)2)n-N^Z2 J (15) -0-(substituted alkyl) wherein said substituted alkyl is substituted with 1 to 3 F atoms, (16) -S(0)t-alkyl, (17) -C(0)-alkyl, (18) N—O—H II ? —C—alkyl (19) N—0—alkyl II -C—alkyl wherein each alkyl is independently selected, (20) o H II N—N—C—alkyl £ II ? —C—alkyl which each alkyl is independently selected, (21) alkyl O II N—N—C—alkyl ? —C—alkyl wherein each alkyl is independently selected, (22) -N(R48)-C(0)-R48 wherein each R48 is independently selected from the group consisting of: H and alkyl, and (23) -C(0)-alkyl: each R3, R4, R5, R6 and R7 is independently selected from the group consisting of: (1) H, (2) alkenyl, RECIEVED IPONZ 22 AUGUST 2011 -483- 3) substituted alkenyl, 4) alkyl, 5) substituted alkyl, 6) cycloalkyl, 7) substituted cycloalkyl, 8) cycloalkylalkyl-, 9) substituted cycloalkylalkyl-, 10) heterocycloalkyl, 11) substituted heterocycloalkyl, 10 (12) heterocycloalkylalkyl-, 13) substituted heterocycloalkylalkyl-, 14) -C(0)R1°, 15) arylheteroaryl-, 16) substituted arylheteroaryl-, 15 (17) heteroarylaryl-, 18) substituted heteroarylaryl-, 19) aryl, 20) substituted aryl, 21) heteroaryl, 20 (22) substituted heteroaryl, 23) heteroarylheteroaryl-, 24) substituted heteroarylheteroaryl-, 25) arylaminoheteroaryl-, 26) substituted arylaminoheteroaryl-, 25 (27) arylalkynyl-, 28) substituted arylalkynyl-, 29) heteroarylalkynyl-, 30) substituted heteroarylalkynyl-, wherein said R3, R4, R5, R6 and R7 substituted groups (7), (9), (11), (13), (16), 30 (18), (20), (22), (24), (26), (28) and (30) are substituted with 1 to 3 substituents independently selected from the group consisting of: -NH2, alkyl, alkenyl, halo, -C(0)-NH-R28, -C(0)0R28, and -C(0)R 28 and RECIEVED IPONZ 22 AUGUST 2011 -484 - wherein said R3, R4, R5, R6 and R7 substituted groups (3) and (5) are substituted with 1 to 3 substituents independently selected from the group consisting of: -NH2, halo, -C(0)-NH-R28, -C(0)0R28, and -C(0)R28; R5a is selected from the group consisting of: halo, -OH, and -O-alkyl; 5 R8 is selected from the group consisting of: H, -OH, -N(R10)2, -NR10C(O)R12, and alkyl; each R9 is independently selected from the group consisting of:halogen, -CN, -N02, -OR10, -SR10, -N(R10)2, and R10; each R10 is independently selected from the group consisting of: H, alkyl, aryl, 10 arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, alkylheteroaryl-, alkylaryl-, substituted alkyl, substituted aryl, substituted arylalkyl, substituted heteroaryl, substituted heteroarylalkyl, substituted cycloalkyl, substituted cycloalkylalkyl, substituted heterocycloalkyl, substituted heterocycloalkylalkyl, substituted alkylheteroaryl-, substituted alkylaryl-, 15 heterocycloalkenyl, and substituted heterocycloalkenyl, and wherein: 1 n said R substituted alkyl is substituted with 1 to 3 substituents independently selected from the group consisting of: -NH2, -NHR20, -N02, -CN, -OR26, halo, -C(0)-NH-R26, -C(0)0R26, and -C(0)R26, and said R10 substituted aryl, substituted arylalkyl, substituted heteroaryl, 20 substituted heteroarylalkyl, substituted cycloalkyl, substituted cycloalkylalkyl, substituted heterocycloalkyl, substituted heterocycloalkylalkyl, substituted alkylheteroaryl- and substituted alkylaryl- are substituted with 1 to 3 substituents independently selected from the group consisting of: (1) -NH2, (2) -N02, (3) -CN, (4) -OH, (5) -OR20, (6) -OCF3, (7) alkyl substituted with 1 to 3 independently selected 25 halo atoms, (8) -C(0)R38, (9) alkyl, (10) alkenyl, (11) halo, (12) -C(0)-NH-R26, (13) -C(0)0R38, (14) -C(O)-NR32-(C(R30)2)n-N(R38)2, (15) -S(0),R38, (16) -C(0)-NR32-R38, (17) -NR32-C(0)-R38, r N R32 (18) S_C_n_R38 J (19) -NHR20, and (20) cycloalkyl; 30 R11 is selected from the group consisting of: F, -OH, -CN, -OR10, -NHNR1R10, -SR10 and heteroaryl; RECIEVED IPONZ 22 AUGUST 2011 -485- R12 is selected from the group consisting of: alkyl, aryl, heteroaryl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl and heterocycloalkylalkyl; R14 is selected from the group consisting of: alkyl, aryl, heteroaryl, cycloalkyl, cycloalkylalkyl-, heterocycloalkyl, alkylheterocycloalkyl, heterocycloalkylalkyl-, 5 alkylheteroaryl- and alkylaryl-; R15 is selected from the group consisting of: H, -OH, alkyl, aryl, heteroaryl, cycloalkyl, cycloalkylalkyl-, heterocycloalkyl and heterocycloalkylalkyl-, alkylheteroaryl-and alkylaryl-; R represents alkyl; po 10 R is selected from the group consisting of: H, alkyl, aryl, cycloalkyl, and cycloalkylalkyl-; each R26 is independently selected from the group consisting of: H and alkyl; R28 is alkyl; on each R is independently selected from the group consisting of: H, alkyl, and 15 F; op each R is independently selected from the group consisting of: H and alkyl, op and wherein each R is generally H; each R35 is independently selected from the group consisting of: H and Ci to C6 alkyl; 20 R36 is selected from the group consisting of: H, alkyl, and -O-alkyl; OQ each R is independently selected from the group consisting of: H, alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, alkylheteroaryl-, alkylaryl-, substituted alkyl, substituted aryl, substituted arylalkyl, substituted heteroaryl, substituted heteroarylalkyl, substituted 25 cycloalkyl, substituted cycloalkylalkyl, substituted heterocycloalkyl, substituted heterocycloalkylalkyl, substituted alkylheteroaryl- and substituted alkylaryl-, and wherein: said R38 substituted alkyl is substituted with 1 to 3 substituents independently selected from the group consisting of: -NH2, -N02, -CN, -OR26, halo, -C(0)-NH-R28, 30 -C(0)0R28, and -C(0)R28, and said R38 substituted aryl, substituted arylalkyl, substituted heteroaryl, substituted heteroarylalkyl, substituted cycloalkyl, substituted cycloalkylalkyl, substituted heterocycloalkyl, substituted heterocycloalkylalkyl, substituted alkylheteroaryl- and substituted alkylaryl- are substituted with 1 to 3 substituents RECIEVED IPONZ 22 AUGUST 2011 -486- independently selected from the group consisting of: (1) -NH2, (2) -N02, (3) -CN, (4) -OH, (5) -OR20, (6) -OCF3, (7) -CF3, (8) -C(0)R26, (9) alkyl, (10) alkenyl, (11) halo, (12) -C(0)-NH-R26, (13) -C(0)0R26, (14) -C(O)-NR32-(C(R30)2)n-N(R26)2, (15) -S(0)tR26, (16) -C(0)N(R32)(R26), (17) -NR32C(0)R26, (19)-NHR20; R42 is selected from the group consisting of: alkyl, aryl, heteroaryl, and cycloalkyl; R44 is selected from the group consisting of: H, alkyl, cycloalkyl, and cycloalkylalkyl; and Each R46 is independently selected from the group consisting of: H, alkyl, cycloalkyl, and cycloalkylalkyl. 2. The compound of Claim 1 having the formula selected from the group consisting of: ; and (1.2) ; and RECIEVED IPONZ 22 AUGUST 2011 -487- >/QjL (13) H r2 '/tl or a pharmaceutically acceptable salt thereof. 3. The compound of Claims 1 or 2, or a pharmaceutically acceptable salt thereof, wherein Q is selected from the group consisting of: 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, and 2.8. 4. The compound of Claims 1 or 2, or a pharmaceutically acceptable salt thereof, wherein Q is selected from the group consisting of: 2.17, 2.18, 2.19, 2.20, 2.21, and 2.22. 5. The compound of Claim 1, or a pharmaceutically acceptable salt thereof, wherein Z1 is -CH2-. 6. The compound of Claim 3, or a pharmaceutically acceptable salt thereof, wherein Q is selected from the group consisting of: moieties 2.1, 2.2, and 2.3. 7. The compound of Claim 6, or a pharmaceutically acceptable salt thereof, wherein Q is selected from the group consisting of: moieties 2.1, 2.2, and 2.3, and 2.3 is selected from the group consisting of: (2.3 A) (2.3B) and (2.3C) 8. The compound of Claims 1 or 7, or a pharmaceutically acceptable salt thereof, wherein each R3, R4, R6, and R7 is independently selected from the group consisting of: H and alkyl. RECIEVED IPONZ 22 AUGUST 2011 -488- 9. The compound of Claim 8, or a pharmaceutically acceptable salt thereof, wherein each R3, R4, R6, and R7 is independently selected from the group consisting of: H and methyl. 5 10. The compound of Claim 9, or a pharmaceutically acceptable salt thereof, wherein each R3, R4, R6, and R7 is H. 11. The compound of Claim 3, or a pharmaceutically acceptable salt thereof, wherein Q is selected from the group consisting of: moieties 2.6 and 2.7. 12. The compound of Claim 11, or a pharmaceutically acceptable salt thereof, wherein Q is selected from the group consisting of: moieties 2.6 and 2.7, and 2.7 is selected from the group consisting of: / RV R6 / RV r6 R\. R6 k r4 r r4 r4 (2.7A) _ (2.7B) and (2.7C) 13. The compound of Claims 1, or 12, or a pharmaceutically acceptable salt thereof, wherein each R3, R4, R6, and R7 is independently selected from the group consisting of: H and alkyl. 20 14. The compound of Claim 13, or a pharmaceutically acceptable salt thereof, wherein each R3, R4, R6, and R7 is independently selected from the group consisting of: H and methyl. 15. The compound of Claim 14, or a pharmaceutically acceptable salt 25 thereof, wherein each R3, R4, R6, and R7 is H. 16. The compound of Claim 10, or a pharmaceutically acceptable salt thereof, wherein Q is 2.1. 10 15 RECIEVED IPONZ 22 AUGUST 2011 -489- 17. The compound of Claim 10, or a pharmaceutically acceptable salt thereof, wherein Q is 2.3B. 18. The compound of Claim 15, or a pharmaceutically acceptable salt 5 thereof, wherein Q is 2.6. 19. The compound of Claim 15, or a pharmaceutically acceptable salt thereof, wherein Q is 2.1k. 10 20. The compound of Claim 15, or a pharmaceutically acceptable salt thereof, wherein Q is 2.7B. 21. The compound of Claim 1, or a pharmaceutically acceptable salt thereof, wherein Q is 2.17. 15 22. The compound of Claim 21, or a pharmaceutically acceptable salt thereof, wherein each R3, R4, R6, and R7 is independently selected from the group consisting of: H and methyl. 22. The compound 3 r-,4 20 23. The compound of Claim 22, or a pharmaceutically acceptable salt thereof, wherein Q is 2.17 wherein each R3, R4, R6, and R7 is H. 24. The compound of any one of Claims 16, 17, 18, 19 or 20, or a pharmaceutically acceptable salt thereof, wherein the compound of formula 1.0 is: r8 25 25. The compound of Claim 2, or a pharmaceutically acceptable salt thereof, wherein the compound of formula 1.0 is a compound of formula 1.3, and Q is selected RECIEVED IPONZ 22 AUGUST 2011 -490- from the group consisting of: 2.1, 2.2, and 2.3, and 2.3 is selected from the group consisting of: r4 (2.3C) (2.3A) (2.3B) and and R3, R4, R6, and R7 are each independently selected from the group consisting of: 5 H and alkyl. 26. The compound of Claim 25, or a pharmaceutically acceptable salt thereof, wherein R3, R4, R6, and R7 are selected from the group consisting of: H and methyl. 10 27. The compound of Claim 26, or a pharmaceirtically acceptable salt thereof, wherein Q is selected from the group consisting of: 2.1 and 2.3B. 28. The compound of Claim 27, or a pharmaceutically acceptable salt 15 thereof, wherein Q is 2.1, and R3, R4, R6, and R7 are each H. 29. The compound of Claim 2, or a pharmaceutically acceptable salt thereof, wherein the compound of formula 1.0 is a compound of formula 1.3, and Q is selected from the group consisting of: 2.6 and 2.7, and 2.7 is selected from the group 20 consisting of: and R3, R4, R6, and R7 are each independently selected from the group consisting of: H and alkyl. (2.7A) (2.7B) and (2-7C) RECIEVED IPONZ 22 AUGUST 2011 -491 - 30. The compound of Claim 29, or a pharmaceutically acceptable salt thereof, wherein R3, R4, R6, and R7 are selected from the group consisting of: H and methyl. 5 31. The compound of Claim 30, or a pharmaceutically acceptable salt thereof, wherein Q is selected from the group consisting of: 2.6, 2.7A and 2.7B. 32. The compound of Claim 31, or a pharmaceutically acceptable salt thereof, wherein Q is 2.6, and R3, R4, R6, and R7 are each H. 10 33. The compound of Claim 31, or a pharmaceutically acceptable salt thereof,wherein Q is 2.1k, and R3, R4, R6, and R7 are each H. 34. The compound of Claim 31, or a pharmaceutically acceptable salt 15 thereof, wherein Q is 2.7B, and R3, R4, R6, and R7 are each H. 35. The compound of Claim 1 wherein Q is selected from the group consisting of: (A) substituted with one or two substituents independently selected from the group 25 consisting of R3 groups, provided that said one or two substitutents are not H; RECIEVED IPONZ 22 AUGUST 2011 15 -492 (C) VN n-r5 substituted with one or two alkyl groups; (D) VN N^R5 substituted with one or two methyl groups; (E) 10 ^^N^R5 substituted with one methyl group; and (F) X. fH3 N .n„ 'r5 . 36. The compound of Claim 1, or a pharmaceutically acceptable salt thereof, wherein Q is selected from the group consisting of: 20 RECIEVED IPONZ 22 AUGUST 2011 -493- (A) N Rb substituted with one or two substituents independently selected from the group consisting of R3 groups, provided that said one or two substitutents are not H; (B) N Rb substituted with one or two alkyl groups; 10 (C) R° substituted with one or two methyl groups; and (D) substituted with one methyl group. 20 37. The compound of any of Claims 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R1 is selected from the group consisting of: >H^i>H S H H S 5—CH2-N—c—<g ' ^—CH2~N—S(0)2CH3' ^—CH2~N—C—N—CH(CH3)2 ' CH2CH3 O O RECIEVED IPONZ 22 AUGUST 2011 -494 - O H II ch2—n—c—n—c2h5 , h h -ch2-n—c—ch3 , 0 h ch2-n—c—ch(ch3)2 II O C=N _ s—cf3 ( s—cooh i <—ch3 , <—ch2oh , <—c=c-ch3 , ch2nh2 , ' s s s j j h b n ^-ish h c! h / \ h n—c—, >-N-C-c3h7i >-n-c-ch3 , -n-ch />, s n Q nh2 j O ^ o ^ o * o — ^ o h h / \ > h h >h n—c—n—(\ » i 5—n—c—n—c2h5 , S—n—s—ch3 o — ^ O S °2 nh s nh c -c—n-oh , s—c-oh - <—c-0-ch3 * 0 c—nh2 > <—c-nh-(ch2)2-0-ch3 " O O -c-nh-(ch2)2-oh o h2 -c—n—c—c—nh? ii h ii 2 O 0 o o -c-n-c-c-nh2 h | ch(ch3)2 h -c-n—ch3 O h -c—n—c4h9 II O h < -c—n—ch(ch3)2 . <—c" II ? II O O » -H n—ch2—v 7 > -c-n—^ ^n > c-n-ch2-^~~^n . ^—c—n—^ ' o \=y o oo RECIEVED IPONZ 22 AUGUST 2011 -495- HO^ h i -c—n—ch II O O HO^ h i -c—n—ch O ^c^ ^ch3 h i -c—n—ch II i O 0^ 0 C^ "-CH3 h i -c—n—ch O >—c-nh-ch2-ch2-o-ch3 * o -c-nh-ch2-ch2-oh o -c-nh-ch2-c-nh2 ii ii o o !-< n o KO N v/WVO 1AAA/1 n—nh hn ^ -N Jl nn ^ n // n—n OX/XIXP IA/V/V h3c c=0 / ■jxjxixr \=J vA/v/v s n- hn S^N ch3 jvw <j\s\s\p \JWV N^ CI n ^ch3 , n ^cf3 och3 RECIEVED IPONZ 22 AUGUST 2011 i/WVP iAAAT -496- JWVP axnjxr n oh , jwv y/v\j\n N^^N N<s^N ' T och3 / n / och3 XT n ii C^°H h 0ch3 och3 r • c=o j T c=o I nh I nh I c2H4 c2h4 n(ch3)2 nh2 CI RECIEVED IPONZ 22 AUGUST 2011 -497- c^ .ch3 cr o o2n h3co2s f3c (h3c)2hc A och3 ch(ch3)2 ocha , och3 c ci hn I 10 0x ch3 % /°X C c ch3 r /A, / o^nh-ch2ch2ch3 hn^c^CH3 ii o RECIEVED IPONZ 22 AUGUST 2011 -498- v/VWP O \- o F, f cf3 och3 ch3 'S-S^v\ / v/V/WV O vCH2ch3 10 ch3 n och3 RECIEVED IPONZ 22 AUGUST 2011 -499- ch3 H2 -c-sr<] /vrw JVVW 0ch3 cf3 n cf3 , / / ^ n _jy n , h3c0 / and N^N / h3c 38. The compound of Claim 1, or a pharmaceutically acceptable salt thereof, wherein R1 is aryl. 10 39. The compound of Claim 1, or a pharmaceutically acceptable salt thereof, wherein R1 is heteroaryl or substituted heteroaryl wherein said substituted heteroaryl is substituted with 1 to 3 substituents independently selected from the group consisting of: (1) -NH2, (2) -N02, (3) -CN, (4) -OH, (5) -OR20, (6) -OCF3, (7) alkyl 15 substituted with 1 to 3 independently selected halo atoms, (8) -C(0)R38, (9) alkyl, (10) alkenyl, (11) halo, (12)-C(0)-NH-R26, (13)-C(0)0R38, (14)-C(O)-NR32-(C(R30)2)n-N(R38)2, (15) -S(0)tR38, (16) -C(0)-NR32-R38, (17) -NR32-C(0)-R38, , n r32 (18) c-n-r38 J (19)-NHR20, and (20) cycloalkyl. 20 40. The compound of Claims 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R5 is selected from the group consisting of: RECIEVED IPONZ 22 AUGUST 2011 -500 NH2 N NH2 , o- /CH3 N H / 10 A a c "ch3, o £ 0^c.0,ch2ch3 A c ch2ch3 , o to to to Br RECIEVED IPONZ 22 AUGUST 2011 41. The compound of Claims 1 or 7, or a pharmaceutically acceptable salt thereof, wherein R1 is selected from the group consisting of: 15 RECIEVED IPONZ 22 AUGUST 2011 -502- h 5 h > h h ch2-n-c—<j ' ch2-n—s(0)2ch3' ch2-n-c-n-ch(ch3)2 -ch2ch3 o o o H ch2—n-c-n-c2h5 , h h -ch2-n—c—ch3 , o l_jj ch2~n—c—ch(ch3)2 : o cen i s—cf3 _ s—cooh _ <—ch3 , q—ch2oh , <—c=c—ch3 , s—ch2nh2 , j 3 s s s h s ^-N-C-C3H7^J-N-C-CH3 ( l-n-c-o ^ o 0 o >—n—c—nh2 , o N-C—N—)> t S—}\j—C—N C2H5 , S-H-s—CH3 O ^ O ^ °2 NH £ NH c -C—N-OH , 5—C-OH > C-O-CH3 * 0 c—nh2 » <—c-nh-(ch2)2-0-ch3 11 o o •C-NH-(CH2)2-0H o h2 -c— n—c—c—nh2 ii h ii o o o o II H II -c—N—C—C—NH2 H j CH(CH3)2 h -c—n—ch3 II O H -C—N—C4H9 II O -C-N-CH(CH3)2 0 h -c—n—ch2-II O // \ RECIEVED IPONZ 22 AUGUST 2011 -503- ~C=/N • bfH-O' ho O h n—ch-^ y • HO^ -c—n—ch $ \ - H A=/ ^ch3 h i -c—n—ch ii £ O ^c-^ ^CH3 h i ■c—n—ch O >—c-nh-ch2-ch2-o-ch3 , ' O -c-nh-ch2-ch2-oh , ii ^ o -c-nh-ch2-c-nh2 M M o o !-< / \ -n o -n KO > N v/VW uxnjxr n—nh n hn *N> n—n 0 10 !AAAT o\r\j\n c=0 h3c k/VW nx "s W vAA/V ^ s n: -CH. hn S'^N / / ' n CI J\T\J\P vAAAT uxnj\n n ch3 , n cf3 , OCH. RECIEVED IPONZ 22 AUGUST 2011 -504 j\j\r\r JVW vAW vAAac n oh , /- Xk o , axnjxr j\ru\r N<s^N n^S^N ' T 0ch3 & ^N n n ii C^ /OH N h f3: c=0 I V c=0 I nh I nh c2h4 I c2h4 n(ch3)2 nh2 RECIEVED IPONZ 22 AUGUST 2011 -505- %och2ch3 ch, n02 ■Cv^ /CH3 o O o2n h3co2s f3c (h3c)2hc och, ch(ch3)2 och3 och3 hn 10 o ch3 °o /°\ c nch3 0^c.nh-CH2CH2CH3 hn^c^.CH3 ii O RECIEVED IPONZ 22 AUGUST 2011 -506- o. ch3 ch3 c xc^ 0 \- o f, f cf, och. fxN r^S ch3 -c=c h h ^O. vAAAA/ "ch2ch3 10 ch3 n och3 RECIEVED IPONZ 22 AUGUST 2011 -507- chq H2 -c-§r<l JVWV f , och, cfq n cf3 , / / h3co / and N^N R is selected from the group consisting of: / h3c f , and 10 .N. ,N. I ^ "nh2 - n -s N^// RECIEVED IPONZ 22 AUGUST 2011 -508- & N W // m 10 n Br ^ .N. N<n N ch2 -cec \\ / k I -cec h ' j h2 -c-c=ch2 h -c—ch3 ii 3 O RECIEVED IPONZ 22 AUGUST 2011 -509- ^ 1 n ch2ch3 and 42. The compound of Claim 41, or a pharmaceutically acceptable salt thereof, wherein R1 is selected from the group consisting of: 43. The compound of Claims 1 or 41, or a pharmaceutically acceptable salt thereof, wherein R2 is selected from the group consisting of: c—h ( <—och3 and <—ch2och3 44. The compound of Claim 41, or a pharmaceutically acceptable salt thereof, wherein Q is selected from the group consisting of: 2.1, 2.2, and 2.3, and 2.3 is selected from the group consisting of: -r4 '" r4 (2.3A) , (2.3B) and (2.3C) and R3, R4, R6, and R7 are each independently selected from the group consisting of: H and alkyl. RECIEVED IPONZ 22 AUGUST 2011 -510 - 45. The compound of Claim 44, or a pharmaceutically acceptable salt thereof, wherein R3, R4, R6, and R7 are each H. 46. The compound of Claim 45, or a pharmaceutically acceptable salt 5 thereof, wherein Q is 2.1. 47. The compound of Claim 41, or a pharmaceutically acceptable salt thereof, wherein Q is selected from the group consisting of: 2.6 and 2.7, and 2.7 is selected from the group consisting of: and R3, R4, R6, and R7 are each independently selected from the group consisting of: H and alkyl. 48. The compound of Claim 47, or a pharmaceutically acceptable salt 15 thereof, wherein R3, R4, R6, and R7 are each H. 49. The compound of Claim 48, or a pharmaceutically acceptable salt thereof, wherein Q is 2.6. 20 50. The compound of Claim 48, or a pharmaceutically acceptable salt thereof, wherein Q is 2.7B. 51. The compound of Claim 41, or a pharmaceutically acceptable salt thereof, wherein Q is selected from the group consisting of: 2.17, 2.18, 2.19, 2.20, 25 2.21, and 2.22, and R3, R4, R6, and R7 are each independently selected from the group consisting of: H and alkyl. 10 (2.7A) (2.7B) and (2-7C) 52. The compound of Claim 1, or a pharmaceutically acceptable salt thereof, wherein Q is RECIEVED IPONZ 22 AUGUST 2011 -511 - 53. The compound of Claim 1 selected from the group consisting of: (A) the final compounds of Examples 1-84, 86-125, 141-418, 420-429, 5 431, 432 and 434-590, 592-609 and 611; (B) the final compounds of Examples 1, 2, 4-61, 65-73, 77-84, 86, 88-98, 100, 102-114, 116-118, 120, 121, 124, 125, 151-155, 159-179, 183, 184, 186, 188-193, 196-199, 202-205, 250, 253-259, 260-299, 301-318, 320-323, 332-347, 356 (Isomer Z), 356 (Isomer E), 357-360, 362, 362 (compound 9P), 364, 368-418, 420- 10 429, 431, 432, 434-436, 440-509, 511 -590, 592-602, 606, 607, 609 and 611; and (C) the final compounds of Examples 6, 100, 183, 184, 186, 188-192, 261, 440-450, and 510-517; or a pharmaceutically acceptable salt thereof. 15 54. The compound of Claim 1 having the formula: N' or a pharmaceutically acceptable salt thereof. 55. The compound of Claim 1 having the formula: 3 \ o 20 RECIEVED IPONZ 22 AUGUST 2011 -512- or a pharmaceutically acceptable salt thereof. 56. The compound of Claim 1 having the formula: or a pharmaceutically acceptable salt thereof. 57. The compound of Claim 1 having the formula: H,C or a pharmaceutically acceptable salt thereof. 58. The compound of Claim 1 having the formula: o or a pharmaceutically acceptable salt thereof. RECIEVED IPONZ 22 AUGUST 2011 -513- 59. The compound of Claim 1 having the formula: or a pharmaceutically acceptable salt thereof. 5 60. The compound of Claim 1 having the formula: ? or a pharmaceutically acceptable salt thereof. 61. The compound of Claim 1 having the formula: or a pharmaceutically acceptable salt thereof. 62. The compound of Claim 1 having the formula: RECIEVED IPONZ 22 AUGUST 2011 -514- or a pharmaceutically acceptable salt thereof. 63. The compound of Claim 1 having the formula: or a pharmaceutically acceptable salt thereof. 64. A pharmaceutical composition comprising at least one compound of any one of Claims 1 to 63, or a pharmaceutically acceptable salt thereof, and a 10 pharmaceutically acceptable carrier. 65. A compound of any one of claims 1 to 63, or a pharmaceutically acceptable salt thereof, for use as a medicament. 15 66. A use of at least one compound of any one of Claims 1 to 63, or a pharmaceutically acceptable salt thereof: (A) for the manufacture of a medicament for treating cancer; (B) for the manufacture of a medicament for treating cancer, wherein said medicament is in a form for administration with at least one chemotherapeutic 20 agent; RECIEVED IPONZ 22 AUGUST 2011 -515- (C) for the manufacture of a medicament for treating cancer, said medicament is in a form for administration with at least one chemotherapeutic agent, and radiation therapy; or (D) and at least one chemotherapeutic agent for the manufacture of a 5 medicament for treating cancer. 67. A use of at least one compound of any one of Claims 1 to 63, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating cancer, wherein said medicament is in a form for administration with at 10 least one chemotherapeutic agent selected from the group consisting of: (1) taxanes, (2) platinum coordinator compounds, (3) epidermal growth factor (EGF) inhibitors that are antibodies, (4) EGF inhibitors that are small molecules, (5) vascular endolithial growth factor (VEGF) inhibitors that are antibodies, (6) VEGF kinase inhibitors that are small molecules, (7) estrogen receptor antagonists or selective estrogen receptor 15 modulators (SERMs), (8) anti-tumor nucleoside derivatives, (9) epothilones, (1.0) topoisomerase inhibitors, (11) vinca alkaloids, (12) antibodies that are inhibitors of aVp3 integrins, (13) folate antagonists, (14) ribonucleotide reductase inhibitors, (15) anthracyclines, (16) biologies; (17) inhibitors of angiogenesis and/or suppressors of tumor necrosis factor alpha (TNF-alpha), (18) Bcr/abl kinase inhibitors, (19) MEK1 20 and/or MEK 2 inhibitors that are small molecules, (20) IGF-1 and IGF-2 inhibitors that are small molecules, (21) small molecule inhibitors of RAF and BRAF kinases, (22) small molecule inhibitors of cell cycle dependent kinases such as CDK1, CDK2, CDK4 and CDK6, (23) alkylating agents, and (24) farnesyl protein transferase inhibitors. 25 68. A use of at least one compound of any one of Claims 1 to 63, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating cancer, wherein said medicament is in a form for administration with at least one signal transduction inhibitor. 30 69. A use of at least one compound of any one of Claims 1 to 63, or a pharmaceutically acceptable salt thereof: (A) for the manufacture of a medicament for treating cancer wherein said cancer is selected from the group consisting of: lung cancer, pancreatic cancer, RECIEVED IPONZ 22 AUGUST 2011 -516- colon cancer, myeloid leukemias, thyroid cancer, myelodysplastic syndrome, bladder carcinoma, epidermal carcinoma, melanoma, breast cancer, prostate cancer, head and neck cancers, ovarian cancer, brain cancers, cancers of mesenchymal origin, sarcomas, tetracarcinomas, nuroblastomas, kidney carcinomas, hepatomas, non-5 Hodgkin's lymphoma, multiple myeloma, and anaplastic thyroid carcinoma; (B) for the manufacture of a medicament for treating cancer wherein said cancer is selected from the group consisting of: melanoma, pancreatic cancer, thryroid cancer, colorectal cancer, lung cancer, breast cancer, and ovarian cancer; (C) for the manufacture of a medicament for treating cancer wherein 10 said medicament is in a form for administration in combination with at least one chemotherapeutic agent, and wherein said cancer is selected from the group consisting of: melanoma, pancreatic cancer, thryroid cancer, colorectal cancer, lung cancer, breast cancer, and ovarian cancer; or (D) in combination with at least one chemotherapeutic agent for the 15 manufacture of a medicament for treating cancer wherein said cancer is selected from the group consisting of: melanoma, pancreatic cancer, thyroid cancer, colorectal cancer, lung cancer, breast cancer, and ovarian cancer. 70 . A use of at least one compound of any one of Claims 1 to 63, or a 20 pharmaceutically acceptable salt thereof: (A) for the manufacture of a medicament for treating melanoma; (B) for the manufacture of a medicament for treating melanoma, wherein said medicament is in a form for administration in combination with at least one chemotherapeutic agent; 25 (B) in combination with at least one chemotherapeutic agent for the manufacture of a medicament for treating melanomas; (C) for the manufacture of a medicament for treating pancreatic cancer; (D) for the manufacture of a medicament for treating pancreatic cancer, wherein said medicament is in a form for administration with at least one 30 chemotherapeutic agent; (D') in combination with at least one chemotherapeutic agent for the manufacture of a medicament for pancreatic cancer; (E) for the manufacture of a medicament for treating thyroid cancer; RECIEVED IPONZ 22 AUGUST 2011 -517- (F) for the manufacture of a medicament for treating thyroid cancer, wherein said medicament is in a form for administration in combination with at least one chemotherapeutic agent; (F) in combination with at least one chemotherapeutic agent for the 5 manufacture of a medicament for treating thyroid cancer; (G) for the manufacture of a medicament for treating colorectal cancer; (H) for the manufacture of a medicament for treating colorectal cancer, wherein said medicament is in a form for administration in combination with at least one chemotherapeutic agent; 10 (H') in combination with at least one chemotherapeutic agent for the manufacture of a medicament for treating colorectal cancer; (I) for the manufacture of a medicament for treating lung cancer; (J) for the manufacture of a medicament for treating lung cancer, wherein said medicament is in a form for administration in combination with at least 15 one chemotherapeutic agent; (J) in combination with at least one chemotherapeutic agent for the manufacture of a medicament for treating lung cancer; (K) for the manufacture of a medicament for treating breast cancer; (L) for the manufacture of a medicament for treating breast cancer, 20 wherein said medicament is in a form for administration in combination with at least one chemotherapeutic agent; (L') in combination with at least one chemotherapeutic agent for the manufacture of a medicament for treating breast cancer; (M) for the manufacture of a medicament for treating ovarian cancer; 25 (N) for the manufacture of a medicament for treating ovarian cancer, wherein said medicament is in a form for administration in combination with at least one chemotherapeutic agent; (N') in combination with at least one chemotherapeutic agent for the manufacture of a medicament for treating ovarian cancer; 30 (O) for the manufacture of a medicament for treating hormone- dependent breast cancer, wherein said medicament is in a form for administration in combination with antihormonal agents; (O') in combination with antihormonal agents for the manufacture of a medicament for treating hormone-dependent breast cancer; RECIEVED IPONZ 22 AUGUST 2011 -518- (P) for the manufacture of a medicament for treating hormone-dependent breast cancer, wherein said medicament is in a form for administration in combination with antihormonal agents, and in combination with at least one chemotherapeutic agent; 5 (P1) in combination with at least one chemotherapeutic agent for the manufacture of a medicament for treating hormone-dependent breast cancer; (Q) for the manufacture of a medicament for preventing hormone-dependent breast cancer, wherein said medicament is in a form for administration in combination with antihormonal agents; 10 (Q') in combination with antihormonal agents for the manufacture of a medicament for treating hormone-dependent breast cancer; (R) for the manufacture of a medicament for preventing hormone-dependent breast cancer, wherein said medicament is in a form for administration in combination with antihormonal agents, and in combination with at least one 15 chemotherapeutic agent; (R') in combination with at least one chemotherapeutic agent for the manufacture of a medicament for preventing hormone-dependent breast cancer; (S) for the manufacture of a medicament for treating brain cancer; (T) for the manufacture of a medicament for treating brain cancer, 20 wherein said medicament is in a form for administration in combination with at least one chemotherapeutic agent; (T) in combination with at least one chemotherapeutic agent for the manufacture of a medicament for treating brain cancer; (U) for the manufacture of a medicament for treating brain cancer, 25 wherein said medicament is in a form for administration in combination with a chemotherapeutic agent wherein said chemotherapeutic agent is temozolomide; (U1) in combination with a chemotherapeutic agent wherein said chemotherapeutic agent is temozolomide for the manufacture of a medicament for treating brain cancer; 30 (V) for the manufacture of a medicament for treating prostate cancer; (W) for the manufacture of a medicament for treating prostate cancer, wherein said medicament is in a form for administration in combination with at least one chemotherapeutic agent; RECIEVED IPONZ 22 AUGUST 2011 -519- (W') in combination with at least one chemotherapeutic agent for the manufacture of a medicament for treating prostate cancer; (X) for the manufacture of a medicament for treating myelodysplastic syndrome ; 5 (Y) for the manufacture of a medicament for treating myelodysplastic syndrome, wherein said medicament is in a form for administration in combination with at least one chemotherapeutic agent; (Y) in combination with at least one chemotherapeutic agent for the manufacture of a medicament for treating myelodysplastic syndrome; 10 (Z) for the manufacture of a medicament for treating myeloid leukemias; (AA) for the manufacture of a medicament for treating myeloid leukemias, wherein said medicament is in a form for administration in combination with at least one chemotherapeutic agent; (AA' in combination with at least one chemotherapeutic agent for the 15 manufacture of a medicament for treating myeloid leukemias; (AB) for the manufacture of a medicament for treating acute myelogenous leukemia; (AC) for the manufacture of a medicament for treating acute myelogenous leukemia, wherein said medicament is in a form for administration in 20 combination with at least one chemotherapeutic agent; (AC') in combination with at least one chemotherapeutic agent for the manufacture of a medicament for treating acute myelogenous leukemia; (AD) for the manufacture of a medicament for treating chronic myelomonocytic leukemia; 25 (AE) for the manufacture of a medicament for treating chronic myelomonocytic leukemia, wherein said medicament is in a form for administration in combination with at least one chemotherapeutic agent; (AE') in combination with at least one chemotherapeutic agent for the manufacture of a medicament for treating chronic myelomonocytic leukemia; 30 (AF) for the manufacture of a medicament for treating chronic myelogenous leukemia; (AG) for the manufacture of a medicament for treating chronic myelogenous leukemia, wherein said medicament is in a form for administration in combination with at least one chemotherapeutic agent; RECIEVED IPONZ 22 AUGUST 2011 -520- (AG) in combination with at least one chemotherapeutic agent for the manufacture of a medicament for treating chronic myelogenous leukemia; (AH) for the manufacture of a medicament for treating bladder cancer; (AI) for the manufacture of a medicament for treating bladder cancer, 5 wherein said medicament is in a form for administration in combination with at least one chemotherapeutic agent; (Al) in combination with at least one chemotherapeutic agent for the manufacture of a medicament for treating bladder cancer; (AJ) for the manufacture of a medicament for treating non-Hodgkin's 10 lymphoma; (AK) for the manufacture of a medicament for treating non-Hodgkin's lymphoma, wherein said medicament is in a form for administration in combination with at least one chemotherapeutic agent; (AK') in combination with at least one chemotherapeutic agent for the 15 . manufacture of a medicament for treating non-Hodgkin's lymphoma; (AL) for the manufacture of a medicament for treating multiple myeloma; (AM) for the manufacture of a medicament for treating multiple myeloma, wherein said medicament is in a form for administration in combination at least one chemotherapeutic agent; or 20 (AM') in combination with at least one chemotherapeutic agent for the manufacture of a medicament for treating multiple myeloma. 71. A pharmaceutical composition comprising at least one compound of any one of claims 1 to 63 or a pharmaceutically acceptable salt thereof, at least one 25 chemotherapeutic agent, and a pharmaceutically acceptable carrier. 72. A pharmaceutical composition comprising at least one compound of any one of claims 1 to 63 or a pharmaceutically acceptable salt thereof, at least one signal transduction inhibitor, and a pharmaceutically acceptable carrier. 30 73. A pharmaceutical composition comprising at least one compound of any one of claims 1 to 63 or a pharmaceutically acceptable salt thereof, at least one antihormonal agent, and a pharmaceutically acceptable carrier. RECIEVED IPONZ 22 AUGUST 2011 -521 - 74. A use of at least one compound of any one of claims 1 to 63 for the manufacture of a medicament for treating cancer wherein the medicament when administered is administered with at least one chemotherapeutic agent. 75. A use of at least one compound of any one of claims 1 to 63 and at least one chemotherapeutic agent for the manufacture of a medicament for treating cancer. 76. A use of claim 74 or claim 75 wherein the cancer is selected from the group consisting of melanoma, pancreatic cancer, thyroid cancer, colorectal cancer, lung cancer, breast cancer, and ovarian cancer. 77. A use as claimed in any one of claims 66 to 70 and 74 to 76 wherein the at least one compound of any one of claims 1 to 63 is present in the medicament in an effective amount. 78. A compound as claimed in any one of claims 1 to 63 and 65, or a pharmaceutically acceptable salt thereof. 79. A pharmaceutical composition as claimed in any one of claims 64 or 71 to 73 substantially as herein described with reference to any example thereof. 80. A use as claimed in any one of claims 66 to 70 and 74 to 77, substantially as herein described with reference to any example thereof. </div>